BIN1

Summary

BIN1 (bridging integrator 1, HGNC:1052) is a protein-coding gene on chromosome 2q14.3, encoding Myc box-dependent-interacting protein 1 (O00499). Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling.

This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor. Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynamin, synaptojanin, endophilin, and clathrin. Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process. Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in several transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described.

Source: NCBI Gene 274 — RefSeq curated summary.

At a glance

• Gene–disease (curated): centronuclear myopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 37
• Clinical variants (ClinVar): 851 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 76
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_139343

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1052
Approved symbol	BIN1
Name	bridging integrator 1
Location	2q14.3
Locus type	gene with protein product
Status	Approved
Aliases	SH3P9, AMPH2
Ensembl gene	ENSG00000136717
Ensembl biotype	protein_coding
OMIM	601248
Entrez	274

Gene structure

Transcript identifiers

Ensembl transcripts: 108 — 105 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000259238, ENST00000316724, ENST00000346226, ENST00000348750, ENST00000351659, ENST00000352848, ENST00000357970, ENST00000376113, ENST00000393040, ENST00000393041, ENST00000409400, ENST00000462958, ENST00000466111, ENST00000484253, ENST00000905632, ENST00000905633, ENST00000905634, ENST00000905635, ENST00000905636, ENST00000905637, ENST00000905638, ENST00000905639, ENST00000905640, ENST00000905641, ENST00000905642, ENST00000905643, ENST00000905644, ENST00000905645, ENST00000905646, ENST00000905647, ENST00000905648, ENST00000905649, ENST00000905650, ENST00000905651, ENST00000905652, ENST00000905653, ENST00000905654, ENST00000905655, ENST00000905656, ENST00000905657, ENST00000905658, ENST00000905659, ENST00000905660, ENST00000905661, ENST00000905662, ENST00000905663, ENST00000905664, ENST00000914476, ENST00000914477, ENST00000914478, ENST00000914479, ENST00000914480, ENST00000914481, ENST00000914482, ENST00000914483, ENST00000914484, ENST00000914485, ENST00000914486, ENST00000914487, ENST00000914488, ENST00000914489, ENST00000914490, ENST00000914491, ENST00000914492, ENST00000947986, ENST00000947987, ENST00000947988, ENST00000947989, ENST00000947990, ENST00000947991, ENST00000947992, ENST00000947993, ENST00000947994, ENST00000947995, ENST00000947996, ENST00000947997, ENST00000947998, ENST00000947999, ENST00000948000, ENST00000948001, ENST00000948002, ENST00000948003, ENST00000948004, ENST00000948005, ENST00000948006, ENST00000948007, ENST00000948008, ENST00000948009, ENST00000948010, ENST00000948011, ENST00000948012, ENST00000948013, ENST00000948014, ENST00000948015, ENST00000948016, ENST00000948017, ENST00000948018, ENST00000948019, ENST00000948020, ENST00000948021, ENST00000948022, ENST00000948023, ENST00000948024, ENST00000948025, ENST00000948026, ENST00000948027, ENST00000948028, ENST00000948029

RefSeq mRNA: 16 — MANE Select: NM_139343 NM_001320632, NM_001320633, NM_001320634, NM_001320640, NM_001320641, NM_001320642, NM_004305, NM_139343, NM_139344, NM_139345, NM_139346, NM_139347, NM_139348, NM_139349, NM_139350, NM_139351

CCDS: CCDS2137, CCDS2138, CCDS2139, CCDS2140, CCDS2141, CCDS2142, CCDS2143, CCDS42743, CCDS42744, CCDS46403, CCDS82508

Canonical transcript exons

ENST00000316724 — 19 exons

Exon	Start	End
ENSE00000925811	127053905	127054012
ENSE00000925822	127068163	127068255
ENSE00000925823	127068924	127069031
ENSE00000925826	127069995	127070090
ENSE00000925827	127070553	127070647
ENSE00000925829	127070762	127070816
ENSE00000925832	127076626	127076706
ENSE00001236385	127052255	127052362
ENSE00001417047	127053422	127053445
ENSE00001918151	127106860	127107154
ENSE00003466327	127051154	127051243
ENSE00003490195	127059011	127059155
ENSE00003552318	127050421	127050522
ENSE00003561195	127063933	127064018
ENSE00003591224	127062115	127062197
ENSE00003605628	127063571	127063646
ENSE00003656910	127057473	127057601
ENSE00003674465	127050802	127050912
ENSE00003845657	127048032	127048633

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.3145 / max 1286.0243, expressed in 1731 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30506	23.5563	1517
30508	4.7516	1275
30511	4.3599	1394
30507	3.9356	994
30493	2.4824	166
30491	0.6514	286
30510	0.5018	277
202377	0.4949	171
30505	0.2880	116
30509	0.2779	89

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	99.70	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.48	gold quality
tibialis anterior	UBERON:0001385	99.47	gold quality
gluteal muscle	UBERON:0002000	99.45	gold quality
skeletal muscle tissue	UBERON:0001134	99.34	gold quality
quadriceps femoris	UBERON:0001377	99.26	gold quality
vastus lateralis	UBERON:0001379	99.25	gold quality
triceps brachii	UBERON:0001509	99.23	gold quality
diaphragm	UBERON:0001103	99.17	gold quality
muscle organ	UBERON:0001630	99.12	gold quality
skeletal muscle organ	UBERON:0014892	99.12	gold quality
deltoid	UBERON:0001476	99.08	gold quality
muscle of leg	UBERON:0001383	99.06	gold quality
biceps brachii	UBERON:0001507	98.98	gold quality
middle frontal gyrus	UBERON:0002702	98.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.83	gold quality
corpus callosum	UBERON:0002336	98.53	gold quality
body of tongue	UBERON:0011876	98.46	gold quality
spinal cord	UBERON:0002240	98.32	gold quality
amygdala	UBERON:0001876	98.27	gold quality
right frontal lobe	UBERON:0002810	98.24	gold quality
putamen	UBERON:0001874	98.19	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.08	gold quality
prefrontal cortex	UBERON:0000451	97.99	gold quality
Ammon’s horn	UBERON:0001954	97.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.98	gold quality
hypothalamus	UBERON:0001898	97.94	gold quality
inferior olivary complex	UBERON:0002127	97.89	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	9.88
E-GEOD-93593	yes	6.64
E-HCAD-5	no	2.24
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MYC	Unknown

Upstream regulators (CollecTRI, top): E2F1, GDNF, MYC, PARP1, SMARCA1, ZBTB17, ZNF354C

miRNA regulators (miRDB)

24 targeting BIN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-548AD-3P	94.39	66.04	350
HSA-MIR-744-5P	93.78	65.29	230
HSA-MIR-6771-5P	86.50	65.30	81

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Missplicing of a brain-specific exon of Bin1 in human melanoma is sufficient to abolish tumor suppressor properties; ectopic WT Bin1 activates PCD in malignant but not normal melanocytes. (PMID:10449755)
• There is frequent downregulation of Bin1 in malignant breast cells; ectopic Bin1 activates PCD in cells lacking expression. (PMID:10652430)
• There is frequent loss or downregulation of Bin1 in metastatic prostate cancer. (PMID:10738240)
• findings support a role of the bilayer-deforming properties of amphiphysin at T-tubules and, more generally, a physiological role of amphiphysin in membrane deformation (PMID:12183633)
• Results document the extent of expression of nuclear Bin1 isoforms, which exhibit cancer suppression and proapoptotic activity in human cells. (PMID:12532338)
• Sorting nexin 4 and amphiphysin 2 have roles in endocytosis and intracellular trafficking (PMID:12668730)
• Studies in mouse indicate that Bin1 is dispensable for endocytosis but essential for appropriate cardiac development. (PMID:12773571)
• role in activating various target genes after induction with the microtubule disrupting agent T113242 (PMID:14704274)
• Phosphoinositides regulate BIN1 SH3 domain binding. (PMID:15483625)
• tumor-specific isoforms of Bin1 are precluded from interaction with c-Myc through an intramolecular polyproline-SH3 domain interaction. Furthermore, c-Myc/Bin1 interaction can be inhibited by phosphorylation of c-Myc at Ser62. (PMID:15992821)
• combination of gene dosages of MYCN and Survivin and the expression level of BIN1 using the quantitative polymerase chain reaction method was significantly correlated with the clinical stage and the patients’ outcome in neuroblastoma (PMID:16516635)
• Crystal structure shows that both the quaternary and tertiary architectures of the homodimeric Bin1 BAR domain are built upon “knobs-into-holes” packing of side chains, and this packing governs the curvature of a putative membrane-engaging concave face. (PMID:17059209)
• Mammary specific deletion of the Bin1 gene cooperates with ras activation to drive mammary tumor progression. The findings establish a role for Bin1 as a negative modifier of oncogenicity and progression in breast cancer. (PMID:17210688)
• Bin1 gene encodes a protein that suppresses neoplastic cell transformation.Bin1 may be a clinical prognostic marker in breast cancer. (PMID:17218774)
• Immunohistochemical losses of nuclear Bin1 proteins in cases of human breast cancer were associated with increased progression status and poor prognosis. (PMID:17218774)
• hob1+, the fission yeast homolog of Bin1, supports a mechanism of Rad6/Set1-dependent transcriptional repression that may relate to cancer suppression by Bin1. (PMID:17611416)
• potential relevance of Bin1-Ku interaction to cancer are discussed in light of these findings (PMID:17671430)
• Mutations in amphiphysin 2 (BIN1) disrupt its membrane tubulation properties and its interaction with dynamin 2, and cause autosomal recessive centronuclear myopathy (PMID:17676042)
• Results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei. (PMID:17676042)
• Mosaic knockout mice lacking Bin1 exhibit lung and liver cancer, increased inflammation or premalignant lesions in prostate, and more progressive colon cancer. Thus, Bin1 suppresses inflammation and cancer during aging. (PMID:17699764)
• Mutated in recessive centronuclear myopathies. (PMID:18154705)
• Results suggest that Bin1 gene suppression caused by oncogenic E1A via Rb/E2F1 inactivation is an essential step in cell cycle progression promoted by c-Myc, and subsequently, E1A transformation. (PMID:18348166)
• findings support models for membrane curving by BAR domains in which helix-0 increases the binding affinity to the membrane and enhances curvature generation (PMID:18658220)
• REVIEW : BIN1 mutations and centronuclear myopathy (PMID:18817572)
• Amphiphysin 2/BIN1 participates in the tubulation of traffic intermediates and intracellular organelles first via its intrinsic tubulating potential and second via its ability to bind CLIP-170 and microtubules. (PMID:19004523)
• Bin1 appears to function as a metastasis suppressor and chemosensitizer in neuroblastoma. (PMID:19418541)
• BIN1 is transcriptionally activated by E2F1 and mediates E2F1-induced apoptosis in response to DNA damage. (PMID:19629135)
• show a requirement for human BIN1 (also known as Amphiphysin 2) in EHD1-regulated endocytic recycling. (PMID:19915558)
• Characterization of amphiphysin 2 membrane tubules in cultured cells with correlative light-electron microscopy (PMID:20140253)
• BIN1 sequencing revealed a homozygous missense mutation in a patient with recessive centronuclear myopathy (PMID:20142620)
• Data have identified that membrane-associated BIN1 not only induces membrane curvature but can direct specific antegrade delivery of microtubule-transported membrane proteins. (PMID:20169111)
• This study shown that established and candidate AD genes have a role in 6 neuroimaging traits linked to AD. 2 promising genes from Alzheimer disease GWASs, CNTN5 and BIN1, are associated with these neuroimaging measures. (PMID:20558387)
• This study proposed that aberrant BIN1 localization and defects in triad structure are part of a common pathogenetic mechanism shared between the three forms of centronuclear myopathies. (PMID:20927630)
• BIN1 polymorphisms were associated with late-onset Alzheimer disease in an independent cohort from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (PMID:21059989)
• We present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. (PMID:21129173)
• we confirmed that BIN1 is a genetic determinants of Alzheimer disease. (PMID:21220176)
• Logistic regression analysis successfully replicates the association of BIN1 (rs744373) with late-onset Alzheimer’s disease, with an odds ratio comparable to that previously reported. (PMID:21321396)
• variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of biomarkers (PMID:21347408)
• There was evidence of association for recently-reported late-onset Alzheimer’s disease risk loci, including BIN1 and CLU and CUGBP2 with APOE. (PMID:21379329)
• A model has been proposed in which increased abundance of c-MYC indirectly leads to decreased BIN1 expression, in turn leading to increased PARP activity and resistance to DNA-damaging agents. (PMID:21447796)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bin1a	ENSDARG00000042114
danio_rerio	bin1b	ENSDARG00000058820
mus_musculus	Bin1	ENSMUSG00000024381
rattus_norvegicus	Bin1	ENSRNOG00000012852
drosophila_melanogaster	Amph	FBGN0027356

Paralogs (3): AMPH (ENSG00000078053), BIN2 (ENSG00000110934), BIN3 (ENSG00000147439)

Protein

Protein identifiers

Myc box-dependent-interacting protein 1 — O00499 (reviewed: O00499)

Alternative names: Amphiphysin II, Amphiphysin-like protein, Box-dependent myc-interacting protein 1, Bridging integrator 1

All UniProt accessions (1): O00499

UniProt curated annotations — full annotation on UniProt →

Function. Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling. Required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling. Is a negative regulator of endocytosis. Is also involved in the regulation of intracellular vesicles sorting, modulation of BACE1 trafficking and the control of amyloid-beta production. In neuronal circuits, endocytosis regulation may influence the internalization of PHF-tau aggregates. May be involved in the regulation of MYC activity and the control cell proliferation. Has actin bundling activity and stabilizes actin filaments against depolymerization in vitro.

Subunit / interactions. Heterodimer with AMPH. Binds SH3GLB1. Interacts (via SH3 domain) with DNM1. Interacts with SYNJ1. Interacts (via SH3 domain) with DNM2. Isoform IIA interacts with CLTC. Isoform IIB does not interact with CLTC. Isoform IIC1 does not interact with CLTC. Isoform IIC2 does not interact with CLTC. Interacts with AP2A2. Interacts with AP2B1. Interacts with MYC (via N-terminal transactivation domain); the interaction requires the integrity of the conserved MYC box regions 1 and 2. Interacts with BIN2. Interacts with SNX4. Interacts (via BAR domain) with BACE1. Binds (via BAR domain) F-actin. (Microbial infection) Interacts (SH3 domain) with HCV NS5A.

Subcellular location. Nucleus. Cytoplasm. Endosome. Cell membrane. Sarcolemma. T-tubule Cytoplasm.

Tissue specificity. Ubiquitous. Highest expression in the brain and muscle. Expressed in oligodendrocytes. Isoform IIA is expressed only in the brain, where it is detected in the gray matter, but not in the white matter. Isoform BIN1 is widely expressed with highest expression in skeletal muscle.

Post-translational modifications. Phosphorylated by protein kinase C.

Disease relevance. Myopathy, centronuclear, 2 (CNM2) [MIM:255200] A congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. The disease is caused by variants affecting the gene represented in this entry. BIN1 mutations have been found in families segregating autosomal dominant centronuclear myopathy. Patients show adult-onset, mildly progressive muscle weakness affecting selected proximal muscles and all distal muscles of the lower limbs.

Isoforms (11)

UniProt ID	Names	Canonical?
O00499-1	IIA	yes
O00499-2	IIB
O00499-3	IIC1
O00499-4	IIC2
O00499-5	IID
O00499-6	II2
O00499-7	II3
O00499-8	BIN1
O00499-9	BIN1-10-13
O00499-10	BIN1-13
O00499-11	BIN1+12A

RefSeq proteins (16): NP_001307561, NP_001307562, NP_001307563, NP_001307569, NP_001307570, NP_001307571, NP_004296, NP_647593, NP_647594, NP_647595, NP_647596, NP_647597, NP_647598, NP_647599, NP_647600, NP_647601 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR003005	Amphiphysin	Family
IPR003023	Amphiphysin_2	Family
IPR004148	BAR_dom	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR035471	Amphiphysin-2_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily

Pfam: PF03114, PF14604

UniProt features (55 total): helix 10, splice variant 8, sequence variant 8, modified residue 7, strand 7, sequence conflict 5, region of interest 4, domain 2, coiled-coil region 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2FIC	X-RAY DIFFRACTION	1.99
1MUZ	SOLUTION NMR
1MV0	SOLUTION NMR
1MV3	SOLUTION NMR
2RMY	SOLUTION NMR
2RND	SOLUTION NMR
5I22	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00499-F1	68.61	0.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (7): 2, 296, 298, 303, 307, 323, 331

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 0 (showing top):

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), endocytosis (GO:0006897), nucleus organization (GO:0006997), cytoskeleton organization (GO:0007010), endosome to lysosome transport (GO:0008333), regulation of cell cycle process (GO:0010564), quinolinate biosynthetic process (GO:0019805), positive regulation of actin filament polymerization (GO:0030838), response to lipopolysaccharide (GO:0032496), T-tubule organization (GO:0033292), positive regulation of apoptotic process (GO:0043065), regulation of neuron differentiation (GO:0045664), positive regulation of endocytosis (GO:0045807), synaptic vesicle endocytosis (GO:0048488), positive regulation of astrocyte differentiation (GO:0048711), lipid tube assembly (GO:0060988), regulation of heart rate by cardiac conduction (GO:0086091), negative regulation of potassium ion transmembrane transport (GO:1901380), negative regulation of amyloid-beta formation (GO:1902430), negative regulation of ventricular cardiac muscle cell action potential (GO:1903946), negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel (GO:1904878), regulation of endocytosis (GO:0030100), cell differentiation (GO:0030154), establishment of localization in cell (GO:0051649)

GO Molecular Function (14): protease binding (GO:0002020), phospholipid binding (GO:0005543), lipid binding (GO:0008289), aspartic-type endopeptidase inhibitor activity (GO:0019828), clathrin binding (GO:0030276), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), tau protein binding (GO:0048156), actin filament binding (GO:0051015), GTPase binding (GO:0051020), protein-folding chaperone binding (GO:0051087), RNA polymerase binding (GO:0070063), protein binding (GO:0005515), protein-containing complex binding (GO:0044877)

GO Cellular Component (24): nucleus (GO:0005634), cytoplasm (GO:0005737), endosome (GO:0005768), cytosol (GO:0005829), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), actin cytoskeleton (GO:0015629), membrane (GO:0016020), Z disc (GO:0030018), T-tubule (GO:0030315), axon (GO:0030424), dendrite (GO:0030425), I band (GO:0031674), vesicle (GO:0031982), node of Ranvier (GO:0033268), axon initial segment (GO:0043194), varicosity (GO:0043196), axon terminus (GO:0043679), cerebellar mossy fiber (GO:0044300), lipid tube (GO:0060987), RNA polymerase II transcription repressor complex (GO:0090571), extrinsic component of synaptic vesicle membrane (GO:0098850), glutamatergic synapse (GO:0098978), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Membrane Trafficking	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	9
enzyme binding	3
binding	3
protein binding	3
main axon	3
vesicle-mediated transport	2
organelle organization	2
presynapse	2
neuron projection	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
lysosomal transport	1
intercellular transport	1
cell cycle process	1
regulation of cell cycle	1
dicarboxylic acid biosynthetic process	1
quinolinate metabolic process	1
pyridine-containing compound biosynthetic process	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
plasma membrane organization	1
muscle cell development	1
membrane organization	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
neuron differentiation	1
regulation of cell differentiation	1
endocytosis	1
regulation of endocytosis	1

Protein interactions and networks

STRING

3223 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BIN1	RIN3	Q8TB24	996
BIN1	SYNJ1	O43426	994
BIN1	MYC	P01106	989
BIN1	DNM1	Q05193	985
BIN1	DNM2	P50570	959
BIN1	BIN3	Q9NQY0	941
BIN1	SYNJ2	O15056	932
BIN1	ITSN1	Q15811	890
BIN1	GRB2	P29354	886
BIN1	PICALM	Q13492	885
BIN1	CLU	P10909	875
BIN1	DPYSL5	Q9BPU6	872
BIN1	ITSN2	Q9NZM3	863
BIN1	PNMA2	Q9UL42	851
BIN1	TRIP10	Q15642	850

IntAct

152 interactions, top by confidence:

A	B	Type	Score
RIN3	BIN1	psi-mi:“MI:0915”(physical association)	0.790
BIN1	RIN3	psi-mi:“MI:0915”(physical association)	0.790
	BIN1	psi-mi:“MI:0915”(physical association)	0.750
BIN1		psi-mi:“MI:0915”(physical association)	0.750
AMPH	BIN1	psi-mi:“MI:0914”(association)	0.740
	BIN1	psi-mi:“MI:0915”(physical association)	0.740
BIN1		psi-mi:“MI:0915”(physical association)	0.740
	BIN1	psi-mi:“MI:0403”(colocalization)	0.740
BIN1		psi-mi:“MI:0403”(colocalization)	0.740
BIN2	BIN1	psi-mi:“MI:0915”(physical association)	0.640
BIN1	BIN2	psi-mi:“MI:0915”(physical association)	0.640
BIN2	BIN1	psi-mi:“MI:0914”(association)	0.640
IRS4	PIK3R2	psi-mi:“MI:0914”(association)	0.640

BioGRID (196): BIN1 (Protein-peptide), BIN1 (Protein-peptide), BIN1 (Protein-peptide), BIN1 (Protein-peptide), DLGAP4 (Reconstituted Complex), XRCC4 (Reconstituted Complex), FBP1 (Reconstituted Complex), DLGAP4 (Two-hybrid), XRCC4 (Two-hybrid), FBP1 (Two-hybrid), BIN1 (Affinity Capture-RNA), BIN1 (Affinity Capture-RNA), BIN1 (Affinity Capture-RNA), BIN1 (Affinity Capture-RNA), MTM1 (Reconstituted Complex)

ESM2 similar proteins: A0A0G2JV04, B0V207, D3Z8X7, D3ZFJ3, D3ZND0, F1LM81, G9CGD6, O00499, O08539, O08839, O12940, O60308, O60784, O75674, O88746, P42567, P55194, Q05DH4, Q0GNC1, Q0IHV1, Q27J81, Q3B7M3, Q3UN70, Q4KLN4, Q505K2, Q5FVK6, Q5T0F9, Q5U3K5, Q66HA5, Q68EF0, Q6P1N0, Q6P5E6, Q6P9Q4, Q6P9Q6, Q80V31, Q80V94, Q8BMI3, Q8BRN9, Q8K1A6, Q8R0H9

Diamond homologs: D3Z6Q9, O00499, O08539, O08838, O08839, P49418, P50478, Q5ZKL7, Q68FR2, Q7TQF7, Q9UBW5, Q95UN8, Q5AFE4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
“MYOD1/SWI/SNF complex”	“up-regulates quantity by expression”	BIN1	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	BIN1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of DNA damage response and repair proteins	6	14.4×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	6	22.9×	2e-04
insulin receptor signaling pathway	5	13.0×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

851 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	374
Likely benign	315
Benign	77

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
158013	NM_139343.3(BIN1):c.1713G>A (p.Trp571Ter)	Pathogenic
8297	NM_139343.3(BIN1):c.105G>T (p.Lys35Asn)	Pathogenic
8298	NM_139343.3(BIN1):c.451G>A (p.Asp151Asn)	Pathogenic
3348477	NM_139343.3(BIN1):c.432del (p.Arg145fs)	Likely pathogenic
3899842	NM_139343.3(BIN1):c.166-2_220+3del	Likely pathogenic
617682	NM_139343.3(BIN1):c.433C>T (p.Arg145Cys)	Likely pathogenic
8299	NM_139343.3(BIN1):c.1723A>T (p.Lys575Ter)	Likely pathogenic

SpliceAI

4671 predictions. Top by Δscore:

Variant	Effect	Δscore
2:127050415:CCTCA:C	donor_loss	1.0000
2:127050416:CTCAC:C	donor_loss	1.0000
2:127050417:TCA:T	donor_loss	1.0000
2:127050418:CACC:C	donor_loss	1.0000
2:127050419:A:C	donor_loss	1.0000
2:127050420:C:CA	donor_loss	1.0000
2:127050420:CCTG:C	donor_gain	1.0000
2:127050518:TGTAC:T	acceptor_gain	1.0000
2:127050519:GTAC:G	acceptor_gain	1.0000
2:127050520:TAC:T	acceptor_gain	1.0000
2:127050521:AC:A	acceptor_gain	1.0000
2:127050522:CC:C	acceptor_gain	1.0000
2:127050526:C:CT	acceptor_gain	1.0000
2:127050797:CTCA:C	donor_loss	1.0000
2:127050798:TCA:T	donor_loss	1.0000
2:127050799:CAC:C	donor_loss	1.0000
2:127051140:C:A	donor_gain	1.0000
2:127051152:A:AC	donor_gain	1.0000
2:127051153:C:CC	donor_gain	1.0000
2:127052375:C:CT	acceptor_gain	1.0000
2:127054028:A:T	acceptor_gain	1.0000
2:127054031:A:T	acceptor_gain	1.0000
2:127057643:A:T	acceptor_gain	1.0000
2:127057652:C:CT	acceptor_gain	1.0000
2:127057653:G:T	acceptor_gain	1.0000
2:127057658:T:C	acceptor_gain	1.0000
2:127057658:T:TC	acceptor_gain	1.0000
2:127059007:CTAC:C	donor_loss	1.0000
2:127059008:TACC:T	donor_loss	1.0000
2:127059009:ACC:A	donor_loss	1.0000

AlphaMissense

3905 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:127048544:G:C	F588L	1.000
2:127048544:G:T	F588L	1.000
2:127048545:A:G	F588S	1.000
2:127048546:A:G	F588L	1.000
2:127048554:G:T	P585H	1.000
2:127048557:A:G	F584S	1.000
2:127048615:C:G	G565R	1.000
2:127048620:A:G	L563P	1.000
2:127048622:C:A	W562C	1.000
2:127048622:C:G	W562C	1.000
2:127048624:A:G	W562R	1.000
2:127048624:A:T	W562R	1.000
2:127050473:A:G	L541P	1.000
2:127050479:A:G	L539P	1.000
2:127063590:A:G	F252S	1.000
2:127063629:A:T	V239D	1.000
2:127063645:G:T	R234S	1.000
2:127063942:A:G	L230P	1.000
2:127063951:A:C	L227R	1.000
2:127063951:A:G	L227P	1.000
2:127063951:A:T	L227Q	1.000
2:127063963:A:G	L223P	1.000
2:127063963:A:T	L223Q	1.000
2:127064005:A:G	L209P	1.000
2:127068188:G:T	A196D	1.000
2:127068220:C:A	W185C	1.000
2:127068220:C:G	W185C	1.000
2:127068222:A:G	W185R	1.000
2:127068222:A:T	W185R	1.000
2:127068982:C:G	R154P	1.000

dbSNP variants (sampled 300 via entrez): RS1000006658 (2:127095864 C>A,T), RS1000010792 (2:127060788 G>A,C), RS1000047177 (2:127073684 C>T), RS1000048384 (2:127055275 G>A,C,T), RS1000059568 (2:127090272 G>A), RS1000086095 (2:127055977 T>C), RS1000091832 (2:127090429 G>A), RS1000105037 (2:127085221 T>A,C), RS1000130804 (2:127102059 CAT>C), RS1000191949 (2:127106103 C>A), RS1000197512 (2:127104597 C>T), RS1000244835 (2:127058154 C>G), RS1000265899 (2:127076303 C>T), RS1000330651 (2:127071470 G>A,T), RS1000396920 (2:127106766 G>A)

Disease associations

OMIM: gene MIM:601248 | disease phenotypes: MIM:255200, MIM:606346

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, centronuclear, 2	Definitive	Autosomal recessive
autosomal recessive centronuclear myopathy	Supportive	Autosomal recessive
autosomal dominant centronuclear myopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
centronuclear myopathy	Definitive	AR
centronuclear myopathy	Limited	AD

Mondo (4): myopathy, centronuclear, 2 (MONDO:0009709), autosomal dominant nonsyndromic hearing loss 22 (MONDO:0011660), autosomal recessive centronuclear myopathy (MONDO:0015705), autosomal dominant centronuclear myopathy (MONDO:0008048)

Orphanet (2): Autosomal recessive centronuclear myopathy (Orphanet:169186), Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome (Orphanet:228012)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000411	Protruding ear
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000750	Delayed speech and language development
HP:0000883	Thin ribs
HP:0001048	Cavernous hemangioma
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001319	Neonatal hypotonia
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001436	Abnormality of the foot musculature
HP:0001511	Intrauterine growth retardation
HP:0001520	Large for gestational age
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000986_1	Alzheimer’s disease (late onset)	3.000000e-10
GCST000986_2	Alzheimer’s disease (late onset)	1.000000e-10
GCST001025_4	Alzheimer’s disease	3.000000e-14
GCST001026_1	Alzheimer’s disease (late onset)	4.000000e-14
GCST001087_5	Alzheimer’s disease	2.000000e-09
GCST001285_7	Psychosis and Alzheimer’s disease	1.000000e-06
GCST001529_5	Alzheimer’s disease	6.000000e-11
GCST002245_6	Alzheimer’s disease (late onset)	7.000000e-44
GCST002463_10	Systemic lupus erythematosus	4.000000e-06
GCST002593_3	Dementia and core Alzheimer’s disease neuropathologic changes	3.000000e-06
GCST002594_23	Neurofibrillary tangles	4.000000e-06
GCST002813_12	Alzheimer’s disease in APOE e4+ carriers	1.000000e-09
GCST002817_19	Alzheimer’s disease in APOE e4- carriers	2.000000e-12
GCST003225_21	Pelvic organ prolapse (moderate/severe)	2.000000e-06
GCST003225_7	Pelvic organ prolapse (moderate/severe)	5.000000e-06
GCST005516_2	Neuritic plaques or neurofibrillary tangles (pleiotropy)	2.000000e-07
GCST005549_1	Alzheimer’s disease (late onset)	5.000000e-08
GCST006014_4	Creatine kinase levels	1.000000e-09
GCST006585_2647	Blood protein levels	1.000000e-07
GCST007319_18	Alzheimer’s disease (late onset)	1.000000e-29
GCST007319_2	Alzheimer’s disease (late onset)	4.000000e-29
GCST007320_108	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-29
GCST007320_5	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-44
GCST007321_4	Family history of Alzheimer’s disease	6.000000e-26
GCST007827_10	Alzheimer’s disease or HDL levels (pleiotropy)	3.000000e-25
GCST009019_1	Alzheimer’s disease	5.000000e-20
GCST009021_18	Alzheimer’s disease	3.000000e-30
GCST009391_1576	Metabolite levels	9.000000e-07
GCST009391_1740	Metabolite levels	5.000000e-06
GCST009391_2066	Metabolite levels	4.000000e-06

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0005940	psychotic symptoms
EFO:0006801	Alzheimer’s disease neuropathologic change
EFO:0006797	neurofibrillary tangles measurement
EFO:0006798	neuritic plaque measurement
EFO:1001870	late-onset Alzheimers disease
EFO:0004534	creatine kinase measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0010349	cholesteryl ester 20:5 measurement
EFO:0010348	cholesteryl ester 20:4 measurement
EFO:0010346	cholesteryl ester 18:3 measurement
EFO:0004980	appendicular lean mass
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C538197	Deafness, autosomal dominant nonsyndromic sensorineural 22 (supp.)
C562934	Myopathy, Centronuclear, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	3
Smoke	decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression	2
Cisplatin	increases response to substance, affects cotreatment, increases expression, decreases activity	2
Doxorubicin	increases response to substance, increases expression, affects binding, decreases activity	2
Hydrogen Peroxide	decreases reaction, increases activity, affects expression, affects binding	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
quinocetone	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one	increases reaction, decreases activity, increases expression, affects binding, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
bisphenol AF	increases expression	1
Bortezomib	increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	increases expression	1
Arsenic	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0JF	KEIOi005-A	Induced pluripotent stem cell	Male
CVCL_D1RS	Abcam U-87MG BIN1 KO	Cancer cell line	Male
CVCL_SF14	HAP1 BIN1 (-) 1	Cancer cell line	Male
CVCL_SF15	HAP1 BIN1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.