Myopathy, centronuclear, 2

Summary

Myopathy, centronuclear, 2 (MONDO:0009709) is a disease caused by BIN1 (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: BIN1 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 698

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, centronuclear, 2
Mondo ID	MONDO:0009709
MeSH	C562934
OMIM	255200
DOID	DOID:0111220
UMLS	C0410204
MedGen	98049
GARD	0015208
Is cancer (heuristic)	no

Also known as: BIN1 centronuclear myopathy · centronuclear myopathy caused by mutation in BIN1 · CNM2 · myopathy, centronuclear, 2 · myopathy, centronuclear, type 2

Data availability: 698 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › centronuclear myopathy › autosomal recessive centronuclear myopathy › myopathy, centronuclear, 2

Related subtypes (1): myopathy, centronuclear, 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

297 uncertain significance, 242 likely benign, 35 conflicting classifications of pathogenicity, 12 benign/likely benign, 10 benign, 2 likely pathogenic, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
158013	NM_139343.3(BIN1):c.1713G>A (p.Trp571Ter)	BIN1	Pathogenic	criteria provided, single submitter
617681	NM_139343.3(BIN1):c.700C>T (p.Arg234Cys)	BIN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3899842	NM_139343.3(BIN1):c.166-2_220+3del	BIN1	Likely pathogenic	criteria provided, single submitter
617682	NM_139343.3(BIN1):c.433C>T (p.Arg145Cys)	BIN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1001992	NM_139343.3(BIN1):c.1461+1G>A	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1157847	NM_139343.3(BIN1):c.1119C>T (p.Thr373=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1305848	NM_139343.3(BIN1):c.775-6C>G	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1335398	NM_139343.3(BIN1):c.1124C>G (p.Pro375Arg)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158007	NM_139343.3(BIN1):c.1132-7T>C	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158011	NM_139343.3(BIN1):c.1625A>G (p.Lys542Arg)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158014	NM_139343.3(BIN1):c.30G>A (p.Thr10=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158021	NM_139343.3(BIN1):c.888C>T (p.Ser296=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1690750	NM_139343.3(BIN1):c.1372-1G>A	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193876	NM_139343.3(BIN1):c.942C>T (p.His314=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210527	NM_139343.3(BIN1):c.1263+11C>T	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
262480	NM_139343.3(BIN1):c.906C>T (p.Gly302=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286314	NM_139343.3(BIN1):c.1371+1G>T	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287351	NM_139343.3(BIN1):c.1353C>T (p.Ala451=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288057	NM_139343.3(BIN1):c.924C>T (p.Pro308=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2906988	NM_139343.3(BIN1):c.958G>A (p.Gly320Ser)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331043	NM_139343.3(BIN1):c.1515C>G (p.Thr505=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331044	NM_139343.3(BIN1):c.1479C>T (p.Val493=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331045	NM_139343.3(BIN1):c.1473T>C (p.Pro491=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331048	NM_139343.3(BIN1):c.1143G>A (p.Pro381=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331050	NM_139343.3(BIN1):c.1131+9C>T	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331051	NM_139343.3(BIN1):c.1047G>A (p.Pro349=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331053	NM_139343.3(BIN1):c.681G>A (p.Leu227=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331055	NM_139343.3(BIN1):c.384G>A (p.Thr128=)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383645	NM_139343.3(BIN1):c.1003-11C>G	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388450	NM_139343.3(BIN1):c.805G>A (p.Gly269Ser)	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 28 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BIN1	Definitive	Autosomal recessive	myopathy, centronuclear, 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BIN1	Orphanet:169186	Autosomal recessive centronuclear myopathy
BIN1	Orphanet:169189	Autosomal dominant centronuclear myopathy
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
CAPN3	Orphanet:267	Calpain-3-related limb-girdle muscular dystrophy R1
CAPN3	Orphanet:565909	Calpain-3-related limb-girdle muscular dystrophy D4
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BIN1	HGNC:1052	ENSG00000136717	O00499	Myc box-dependent-interacting protein 1	gencc,clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
CAPN3	HGNC:1480	ENSG00000092529	P20807	Calpain-3	clinvar
LIMS2	HGNC:16084	ENSG00000072163	Q7Z4I7	LIM and senescent cell antigen-like-containing domain protein 2	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
ASIC4-AS1	HGNC:40960	ENSG00000227432		ASIC4 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BIN1	Myc box-dependent-interacting protein 1	Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
CAPN3	Calpain-3	Calcium-regulated non-lysosomal thiol-protease.
LIMS2	LIM and senescent cell antigen-like-containing domain protein 2	Adapter protein in a cytoplasmic complex linking beta-integrins to the actin cytoskeleton, bridges the complex to cell surface receptor tyrosine kinases and growth factor receptors.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	6.1×	0.396
Antibody/Immunoglobulin	1	4.9×	0.396
Kinase	1	4.6×	0.396
Scaffold/PPI	1	2.9×	0.451
Transcription factor	1	1.4×	0.647
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BIN1	Scaffold/PPI	no		SH3_domain, Amphiphysin, Amphiphysin_2
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
CAPN3	Protease	yes	3.4.22.54	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom
LIMS2	Transcription factor	no		Znf_LIM, PINCH-1-4-like, LIMS1/2-like_LIM1
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
ASIC4-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
gastrocnemius	1
skeletal muscle tissue of rectus abdominis	1
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
C1 segment of cervical spinal cord	1
skeletal muscle tissue	1
apex of heart	1
lower esophagus	1
lower esophagus muscularis layer	1
popliteal artery	1
right coronary artery	1
tibial artery	1
islet of Langerhans	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BIN1	287	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
CAPN3	134	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, C1 segment of cervical spinal cord
LIMS2	237	ubiquitous	marker	apex of heart, lower esophagus muscularis layer, lower esophagus
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
ASIC4-AS1	115		yes	male germ line stem cell (sensu Vertebrata) in testis, islet of Langerhans, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321
TTN	4,237
BIN1	3,571
CAPN3	1,977
LIMS2	743
ASIC4-AS1	0

Intra-cohort edges

A	B	Sources
CAPN3	TTN	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
FLNA	P21333	26
BIN1	O00499	7
CAPN3	P20807	5
LIMS2	Q7Z4I7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 6 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cell-extracellular matrix interactions	2	268.7×	3e-04	LIMS2, FLNA
Platelet degranulation	2	35.1×	0.008	TTN, FLNA
OAS antiviral response	1	253.8×	0.017	FLNA
GP1b-IX-V activation signalling	1	190.3×	0.017	FLNA
RHO GTPases activate PAKs	1	108.8×	0.024	FLNA
Striated Muscle Contraction	1	61.7×	0.035	TTN
Cell junction organization	1	37.4×	0.049	LIMS2
Cell-Cell communication	1	27.5×	0.058	LIMS2
Degradation of the extracellular matrix	1	23.6×	0.060	CAPN3
Clathrin-mediated endocytosis	1	17.0×	0.075	BIN1
Extracellular matrix organization	1	12.6×	0.091	CAPN3
Membrane Trafficking	1	7.4×	0.136	BIN1
Vesicle-mediated transport	1	7.0×	0.136	BIN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of integrin-mediated signaling pathway	2	518.5×	6e-04	LIMS2, FLNA
sarcomere organization	2	153.2×	0.003	TTN, CAPN3
positive regulation of substrate adhesion-dependent cell spreading	2	149.8×	0.003	LIMS2, FLNA
response to calcium ion	2	127.2×	0.003	TTN, CAPN3
negative regulation of ventricular cardiac muscle cell action potential	1	3370.4×	0.003	BIN1
negative regulation of cholangiocyte proliferation	1	3370.4×	0.003	LIMS2
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	3370.4×	0.003	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	3370.4×	0.003	FLNA
calcium-dependent self proteolysis	1	3370.4×	0.003	CAPN3
negative regulation of apoptotic process	3	20.9×	0.003	CAPN3, LIMS2, FLNA
positive regulation of satellite cell activation involved in skeletal muscle regeneration	1	1685.2×	0.005	CAPN3
lipid tube assembly	1	1685.2×	0.005	BIN1
cholangiocyte proliferation	1	1685.2×	0.005	LIMS2
skeletal muscle myosin thick filament assembly	1	1123.5×	0.006	TTN
sarcomerogenesis	1	1123.5×	0.006	TTN
tubulin deacetylation	1	1123.5×	0.006	FLNA
negative regulation of hepatocyte proliferation	1	1123.5×	0.006	LIMS2
formation of radial glial scaffolds	1	842.6×	0.007	FLNA
cellular response to salt stress	1	842.6×	0.007	CAPN3
negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	842.6×	0.007	BIN1
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	674.1×	0.007	FLNA
establishment of Sertoli cell barrier	1	674.1×	0.007	FLNA
skeletal muscle thin filament assembly	1	561.7×	0.008	TTN
T-tubule organization	1	561.7×	0.008	BIN1
G1 to G0 transition involved in cell differentiation	1	561.7×	0.008	CAPN3
protein localization to bicellular tight junction	1	561.7×	0.008	FLNA
negative regulation of transcription by RNA polymerase I	1	481.5×	0.008	FLNA
detection of muscle stretch	1	481.5×	0.008	TTN
regulation of myoblast differentiation	1	481.5×	0.008	CAPN3
blood coagulation, intrinsic pathway	1	421.3×	0.009	FLNA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLNA	1	2
BIN1	0	0
TTN	0	0
CAPN3	0	0
LIMS2	0	0
ASIC4-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	FLNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FLNA	7	Binding:7
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
CAPN3	3.4.22.54, 3.4.22.56	calpain-3, caspase-3

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	FLNA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	FLNA
C	Druggable family + PDB, no drug	2	TTN, CAPN3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	BIN1, LIMS2, ASIC4-AS1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BIN1	0	—
TTN	1	—
CAPN3	0	—
LIMS2	0	—
ASIC4-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.