BABAM2

Summary

BABAM2 (BRISC and BRCA1 A complex member 2, HGNC:1106) is a protein-coding gene on chromosome 2p23.2, encoding BRISC and BRCA1-A complex member 2 (Q9NXR7). Component of the BRCA1-A complex, a complex that specifically recognizes ‘Lys-63’-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs).

This gene encodes an anti-apoptotic, death receptor-associated protein that interacts with tumor necrosis factor-receptor-1. The encoded protein acts as an adapter in several protein complexes, including the BRCA1-A complex and the BRISC complex. The BRCA1-A complex possesses ubiquitinase activity and targets sites of double strand DNA breaks, while the BRISC complex exhibits deubiquitinase activity and is involved in mitotic spindle assembly. This gene is upregulated in several types of cancer.

Source: NCBI Gene 9577 — RefSeq curated summary.

At a glance

• GWAS associations: 27
• Clinical variants (ClinVar): 71 total
• MANE Select transcript: NM_199191

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1106
Approved symbol	BABAM2
Name	BRISC and BRCA1 A complex member 2
Location	2p23.2
Locus type	gene with protein product
Status	Approved
Aliases	BRCC45, BRCC4
Ensembl gene	ENSG00000158019
Ensembl biotype	protein_coding
OMIM	610497
Entrez	9577

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 25 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 non_stop_decay

ENST00000342045, ENST00000344773, ENST00000361704, ENST00000379624, ENST00000379629, ENST00000379632, ENST00000436924, ENST00000492702, ENST00000496951, ENST00000603461, ENST00000604932, ENST00000873731, ENST00000873732, ENST00000873733, ENST00000873734, ENST00000873735, ENST00000918536, ENST00000918537, ENST00000918538, ENST00000968061, ENST00000968062, ENST00000968063, ENST00000968064, ENST00000968065, ENST00000968066, ENST00000968067, ENST00000968068, ENST00000968069, ENST00000968070

RefSeq mRNA: 10 — MANE Select: NM_199191 NM_001261840, NM_001329112, NM_001329113, NM_001329114, NM_001329115, NM_004899, NM_199191, NM_199192, NM_199193, NM_199194

CCDS: CCDS1763, CCDS1764, CCDS1765

Canonical transcript exons

ENST00000379624 — 12 exons

Exon	Start	End
ENSE00001255657	27890729	27890842
ENSE00001591293	28237202	28237301
ENSE00001644605	28045725	28045799
ENSE00001654219	28241323	28241393
ENSE00001686271	28129271	28129380
ENSE00001696372	28244780	28244862
ENSE00001792274	28025226	28025420
ENSE00001795056	28298338	28298491
ENSE00003490020	28338450	28338901
ENSE00003544418	27987993	27988087
ENSE00003562536	27929832	27929908
ENSE00003668458	27894533	27894684

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.6925 / max 1095.0107, expressed in 1820 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19409	41.0465	1820
19420	1.9413	591
19410	0.2493	53
19408	0.2267	88
19407	0.1525	55
19406	0.0762	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.16	gold quality
left adrenal gland cortex	UBERON:0035825	99.06	gold quality
right adrenal gland cortex	UBERON:0035827	99.01	gold quality
left adrenal gland	UBERON:0001234	98.99	gold quality
adrenal cortex	UBERON:0001235	98.33	gold quality
adrenal gland	UBERON:0002369	98.09	gold quality
adrenal tissue	UBERON:0018303	95.42	gold quality
gastrocnemius	UBERON:0001388	94.86	gold quality
right atrium auricular region	UBERON:0006631	94.69	gold quality
popliteal artery	UBERON:0002250	94.35	gold quality
tibial artery	UBERON:0007610	94.34	gold quality
muscle of leg	UBERON:0001383	94.30	gold quality
heart left ventricle	UBERON:0002084	94.01	gold quality
cardiac atrium	UBERON:0002081	93.92	gold quality
cardiac ventricle	UBERON:0002082	93.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.55	gold quality
heart	UBERON:0000948	93.38	gold quality
aorta	UBERON:0000947	93.13	gold quality
adenohypophysis	UBERON:0002196	93.12	gold quality
apex of heart	UBERON:0002098	93.08	gold quality
metanephros cortex	UBERON:0010533	93.08	gold quality
gall bladder	UBERON:0002110	92.97	gold quality
islet of Langerhans	UBERON:0000006	92.93	gold quality
adult mammalian kidney	UBERON:0000082	92.93	gold quality
left ovary	UBERON:0002119	92.84	gold quality
smooth muscle tissue	UBERON:0001135	92.57	gold quality
decidua	UBERON:0002450	92.51	gold quality
omental fat pad	UBERON:0010414	92.41	gold quality
peritoneum	UBERON:0002358	92.37	gold quality
muscle organ	UBERON:0001630	92.35	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	28.73
E-ANND-3	yes	9.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, NR4A1, RARA

miRNA regulators (miRDB)

17 targeting BABAM2, 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-4267	99.96	66.53	2368
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-876-5P	97.99	68.49	1345
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-6866-5P	96.64	68.06	624
HSA-MIR-4462	95.10	66.27	172
HSA-MIR-3130-3P	94.98	66.97	574
HSA-MIR-6763-3P	90.80	64.32	80

Literature-anchored findings (GeneRIF, showing 14)

• BRE mediates antiapoptosis by inhibiting the mitochondrial apoptotic machinery (PMID:15465831)
• the enhanced tumor growth is more likely due to the antiapoptotic activity of BRE than any direct effect of the protein on cell proliferation (PMID:15582573)
• Antiapoptotic in vivo; Bre levels are regulated post-transcriptionally in the liver, which is not observed in human hepatocellular carcinoma (HCC) and non-HCC cell lines. (PMID:17704801)
• results implied that BRE plays a significant role in mediating antiapoptotic and proliferative responses in esophageal carcinoma cells (PMID:18756325)
• A novel stress-responsive gene called BRE which interacts with TNF-receptor-1 and blocks the apoptotic effect of TNF-alpha, was identified. (PMID:19757177)
• These results show that BRE over-expression can indeed promote growth, though not initiation, of liver tumors. (PMID:20035718)
• overexpression of the BRE gene is predominantly found in MLL-rearranged AML with t(9;11)(p22;q23). (PMID:20861917)
• NBA1/MERIT40 and BRE interaction is required for the integrity of two distinct deubiquitinating enzyme BRCC36-containing complexes (PMID:21282113)
• High BRE expression defines a novel subtype of adult acute myeloid leukemia characterized by a favorable prognosis. (PMID:21937695)
• High BRE and high EVI1 expression are mutually exclusive in MLL-AF9-positive acute myeloid leukemia patients. (PMID:22555662)
• Results show that BRE expression is regulated by HOTTIP LncRNA. Its over-expression promotes cell proliferation and cell cycle progression inhibiting apoptosis of glioma cells. (PMID:27733185)
• C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML. (PMID:28871137)
• show that BRE facilitates deubiquitylation of CDC25A by recruiting ubiquitin-specific-processing protease 7 (USP7) in the presence of DNA damage (PMID:29416040)
• The BRE rs7572644 and NRG3 rs1649942 genetic variants were validated in an independent cohort of EOC Portuguese patients. (PMID:30287910)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	babam2	ENSDARG00000038863
mus_musculus	Babam2	ENSMUSG00000052139
rattus_norvegicus	Babam2	ENSRNOG00000004364

Protein

Protein identifiers

BRISC and BRCA1-A complex member 2 — Q9NXR7 (reviewed: Q9NXR7)

Alternative names: BRCA1-A complex subunit BRE, BRCA1/BRCA2-containing complex subunit 45, Brain and reproductive organ-expressed protein

All UniProt accessions (4): Q9NXR7, A0A075B7D2, C9J2G0, F8W733

UniProt curated annotations — full annotation on UniProt →

Function. Component of the BRCA1-A complex, a complex that specifically recognizes ‘Lys-63’-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes ‘Lys-63’-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer. Component of the BRISC complex, a multiprotein complex that specifically cleaves ‘Lys-63’-linked ubiquitin in various substrates. Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1. The BRISC complex plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination. May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF signaling through its interactions with TNFRSF1A; however these effects may be indirect.

Subunit / interactions. Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1, BRCC3/BRCC36 and BABAM1/NBA1. Binds polyubiquitin. Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with SHMT2 and the other subunits of the BRISC complex. Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BRCC3/BRCC36 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. May interact with FAS and TNFRSF1A.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in all cell lines examined. Highly expressed in placenta.

Domain organisation. Contains 2 ubiquitin-conjugating enzyme family-like (UEV-like) regions. These regions lack the critical Cys residues required for ubiquitination but retain the ability to bind ubiquitin.

Induction. Down-regulated by DNA-damaging agents in fibroblasts, by retinoic acid in brain glioma U-251MG and promyelocytic HL-60 cell lines, and by bacterial lipopolysaccharides (LPS) in peripheral blood mononuclear cells (PBMC).

Similarity. Belongs to the BABAM2 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NXR7-2	2	yes
Q9NXR7-1	1
Q9NXR7-3	3, Alpha a’
Q9NXR7-4	4

RefSeq proteins (10): NP_001248769, NP_001316041, NP_001316042, NP_001316043, NP_001316044, NP_004890, NP_954661, NP_954662, NP_954663, NP_954664 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010358	BRE	Family

Pfam: PF06113

UniProt features (37 total): strand 11, helix 9, turn 8, splice variant 3, region of interest 2, modified residue 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8PVY	ELECTRON MICROSCOPY	3.02
8PY2	ELECTRON MICROSCOPY	3.32
6R8F	ELECTRON MICROSCOPY	3.8
6H3C	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXR7-F1	92.76	0.79

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 (2): 1, 2

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-5689901	Metalloprotease DUBs
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-1640170	Cell Cycle
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-5693606	DNA Double Strand Break Response
R-HSA-597592	Post-translational protein modification
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73894	DNA Repair

MSigDB gene sets: 228 (showing top): ATF_B, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_RESPONSE_TO_IONIZING_RADIATION, GAANYNYGACNY_UNKNOWN, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, CTAGGAA_MIR384, MARTINEZ_RB1_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS

GO Biological Process (16): regulation of DNA repair (GO:0006282), double-strand break repair (GO:0006302), chromatin organization (GO:0006325), apoptotic process (GO:0006915), DNA damage response (GO:0006974), mitotic G2 DNA damage checkpoint signaling (GO:0007095), signal transduction (GO:0007165), response to ionizing radiation (GO:0010212), negative regulation of apoptotic process (GO:0043066), mitotic G2/M transition checkpoint (GO:0044818), positive regulation of DNA repair (GO:0045739), cell division (GO:0051301), protein K63-linked deubiquitination (GO:0070536), cellular response to ionizing radiation (GO:0071479), regulation of DNA damage checkpoint (GO:2000001), DNA repair (GO:0006281)

GO Molecular Function (4): peroxisome signal sequence receptor activity (GO:0000268), tumor necrosis factor receptor binding (GO:0005164), polyubiquitin modification-dependent protein binding (GO:0031593), protein binding (GO:0005515)

GO Cellular Component (7): nuclear ubiquitin ligase complex (GO:0000152), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), BRCA1-A complex (GO:0070531), BRISC complex (GO:0070552)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
DNA Double-Strand Break Repair	3
Deubiquitination	1
DNA Double Strand Break Response	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1
Post-translational protein modification	1
DNA Repair	1
Homology Directed Repair	1
Metabolism of proteins	1
Cell Cycle Checkpoints	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA repair	3
nuclear protein-containing complex	3
cellular anatomical structure	3
regulation of cellular response to stress	2
cellular process	2
regulation of DNA metabolic process	1
cellular component organization	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to radiation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
mitotic cell cycle checkpoint signaling	1
negative regulation of G2/M transition of mitotic cell cycle	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
protein deubiquitination	1
response to ionizing radiation	1
cellular response to radiation	1
DNA damage checkpoint signaling	1
regulation of cell cycle checkpoint	1
DNA metabolic process	1
DNA damage response	1
signal sequence receptor activity	1
tumor necrosis factor receptor superfamily binding	1
modification-dependent protein binding	1
binding	1
ubiquitin ligase complex	1
nucleus	1

Protein interactions and networks

STRING

1320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BABAM2	BRCC3	P46736	998
BABAM2	BABAM1	Q9NWV8	998
BABAM2	ABRAXAS1	Q6UWZ7	997
BABAM2	UIMC1	Q96RL1	997
BABAM2	BARD1	Q99728	995
BABAM2	BRCA1	P38398	995
BABAM2	ABRAXAS2	Q15018	993
BABAM2	RAD51	Q06609	814
BABAM2	BRCA2	P51587	704
BABAM2	UBE2D1	P51668	640
BABAM2	RNF8	O76064	621
BABAM2	GTF2B	Q00403	608
BABAM2	ATM	Q13315	559
BABAM2	FANCG	O15287	528
BABAM2	CSTF1	Q05048	522

IntAct

87 interactions, top by confidence:

A	B	Type	Score
BABAM2	BABAM1	psi-mi:“MI:0915”(physical association)	0.920
BABAM1	BABAM2	psi-mi:“MI:0915”(physical association)	0.920
BABAM1	BABAM2	psi-mi:“MI:2364”(proximity)	0.920
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
BABAM2	BRCC3	psi-mi:“MI:0914”(association)	0.670
BABAM1	TNKS	psi-mi:“MI:0914”(association)	0.640
BABAM2	SHMT2	psi-mi:“MI:0914”(association)	0.640
BRCA1	BRCC3	psi-mi:“MI:0914”(association)	0.610
SMAD4	BABAM2	psi-mi:“MI:0915”(physical association)	0.550
SMAD4	BABAM2	psi-mi:“MI:2364”(proximity)	0.550
DEF6	ARHGAP42	psi-mi:“MI:0914”(association)	0.530
C9orf85	BRCC3	psi-mi:“MI:0914”(association)	0.530
FOXRED2	CLGN	psi-mi:“MI:0914”(association)	0.530
BABAM2	EGFR	psi-mi:“MI:2364”(proximity)	0.480

BioGRID (213): BRE (Affinity Capture-Western), BRE (Affinity Capture-MS), BRE (Affinity Capture-MS), BRE (Affinity Capture-MS), CHI3L1 (Affinity Capture-MS), BABAM1 (Two-hybrid), BRE (Co-fractionation), BRE (Proximity Label-MS), BRE (Affinity Capture-MS), BRE (Affinity Capture-Western), BRE (Affinity Capture-MS), BRE (Affinity Capture-MS), BRE (Affinity Capture-MS), BRE (Affinity Capture-MS), SHMT2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IES7, A0JN62, A2AAE1, A2RV80, A4IFQ0, A6QQW8, F1Q8X5, O35382, P48553, P70398, Q08BT5, Q13769, Q2LD37, Q5F361, Q5R903, Q5RAQ5, Q5REX9, Q62824, Q68FX7, Q6DFZ1, Q6IC98, Q6NRC7, Q6P6Y1, Q6SP92, Q6ZWH5, Q7SXV1, Q7TSG1, Q7Z7G8, Q80TY5, Q8BHY8, Q8BKT7, Q8BQZ4, Q8CB44, Q8CIB5, Q8K3W0, Q8N960, Q8WN69, Q8WN70, Q91W96, Q92538

Diamond homologs: A6QQW8, B6NXD5, Q568D5, Q5REX9, Q5ZML0, Q6DJ78, Q6GPL9, Q6P7Q1, Q6SP92, Q8K3W0, Q8WN69, Q8WN70, Q9NXR7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
BABAM2	“form complex”	“BRCC ubiquitin ligase complex”	binding
BABAM2	“form complex”	“BRCA1-A complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 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
Metalloprotease DUBs	6	37.6×	2e-06
Nonhomologous End-Joining (NHEJ)	7	24.5×	2e-06
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	8	24.4×	7e-07
Regulation of PTEN stability and activity	6	23.0×	2e-05
G2/M DNA damage checkpoint	8	20.0×	2e-06
G2/M Checkpoints	7	19.6×	6e-06
Processing of DNA double-strand break ends	7	16.6×	2e-05
Deubiquitination	6	15.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of DNA repair	6	37.1×	1e-05
epidermal growth factor receptor signaling pathway	5	21.4×	7e-04
double-strand break repair	6	21.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

5382 predictions. Top by Δscore:

Variant	Effect	Δscore
2:27890517:T:TA	donor_gain	1.0000
2:27890830:GAC:G	donor_gain	1.0000
2:27929408:GC:G	donor_gain	1.0000
2:27929812:T:TA	acceptor_gain	1.0000
2:27929818:T:A	acceptor_gain	1.0000
2:27929821:A:AG	acceptor_gain	1.0000
2:27929822:T:G	acceptor_gain	1.0000
2:27929828:A:AG	acceptor_gain	1.0000
2:27929905:AAGT:A	donor_gain	1.0000
2:27929905:AAGTG:A	donor_loss	1.0000
2:27929906:AGTG:A	donor_loss	1.0000
2:27929907:GT:G	donor_gain	1.0000
2:27929907:GTGTA:G	donor_loss	1.0000
2:27929908:TG:T	donor_loss	1.0000
2:27929909:G:GG	donor_gain	1.0000
2:27929909:G:T	donor_loss	1.0000
2:27929910:T:A	donor_loss	1.0000
2:27929911:AA:A	donor_loss	1.0000
2:27929912:AGTA:A	donor_loss	1.0000
2:27987990:CAG:C	acceptor_loss	1.0000
2:27987991:A:AC	acceptor_loss	1.0000
2:27987991:A:AG	acceptor_gain	1.0000
2:27987991:AG:A	acceptor_gain	1.0000
2:27987991:AGG:A	acceptor_gain	1.0000
2:27987991:AGGG:A	acceptor_gain	1.0000
2:27987992:G:GA	acceptor_gain	1.0000
2:27987992:G:T	acceptor_loss	1.0000
2:27987992:GG:G	acceptor_gain	1.0000
2:27987992:GGG:G	acceptor_gain	1.0000
2:27987992:GGGG:G	acceptor_gain	1.0000

AlphaMissense

2504 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:27929867:G:C	R55P	1.000
2:27929876:T:C	L58P	1.000
2:27929908:T:A	W69R	1.000
2:27929908:T:C	W69R	1.000
2:27988032:C:A	P82H	1.000
2:27988032:C:G	P82R	1.000
2:28025238:T:A	W105R	1.000
2:28025238:T:C	W105R	1.000
2:28025284:T:C	L120P	1.000
2:28025295:T:G	Y124D	1.000
2:28025343:T:C	F140L	1.000
2:28025345:T:A	F140L	1.000
2:28025345:T:G	F140L	1.000
2:28045747:T:C	F173S	1.000
2:28129302:C:A	A201D	1.000
2:28129308:T:A	L203H	1.000
2:28129308:T:C	L203P	1.000
2:28129314:T:A	V205D	1.000
2:28129356:T:A	L219Q	1.000
2:28129356:T:C	L219P	1.000
2:28237258:T:A	L246H	1.000
2:28237258:T:C	L246P	1.000
2:28237270:T:A	V250D	1.000
2:28237288:T:C	L256P	1.000
2:28237291:T:A	L257H	1.000
2:28237291:T:C	L257P	1.000
2:28241354:G:C	R271T	1.000
2:28241354:G:T	R271I	1.000
2:28241355:A:C	R271S	1.000
2:28241355:A:T	R271S	1.000

dbSNP variants (sampled 300 via entrez): RS1000000757 (2:28187175 A>T), RS1000007139 (2:28072573 G>A,C), RS1000013223 (2:28332628 C>A,T), RS1000017453 (2:28090354 C>T), RS1000017628 (2:28294579 T>A), RS1000019664 (2:28134538 G>C), RS1000024551 (2:27931484 C>A,T), RS1000039557 (2:28026362 G>T), RS1000039771 (2:27945457 CT>C), RS1000044811 (2:28018798 C>T), RS1000046750 (2:28287900 A>G), RS1000070235 (2:28308074 G>A,T), RS1000098344 (2:28224789 C>T), RS1000104923 (2:28072616 A>C), RS1000113405 (2:27924916 T>C)

Disease associations

OMIM: gene MIM:610497 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST001725_42	Inflammatory bowel disease	3.000000e-15
GCST002137_2	Waist circumference	2.000000e-07
GCST003048_130	Schizophrenia	4.000000e-08
GCST003088_2	Soluble interleukin-2 receptor subunit alpha	6.000000e-06
GCST003443_3	Response to carboplatin and paclitaxel in ovarian cancer (Caspase 3/7 EC50)	6.000000e-06
GCST004011_1	RR interval (tricyclic/tetracyclic antidepressant use interaction)	8.000000e-09
GCST005312_31	Menopause (age at onset)	2.000000e-15
GCST005580_5	Intraocular pressure	2.000000e-15
GCST005580_8	Intraocular pressure	4.000000e-15
GCST006394_33	Intraocular pressure	2.000000e-09
GCST006412_17	Intraocular pressure	1.000000e-09
GCST006988_81	Blond vs. brown/black hair color	4.000000e-09
GCST008059_191	Estimated glomerular filtration rate	8.000000e-12
GCST008103_38	Bipolar disorder	1.000000e-07
GCST008103_50	Bipolar disorder	3.000000e-07
GCST008972_187	Urate levels	9.000000e-15
GCST009158_8	Uterine fibroids	6.000000e-09
GCST009391_1831	Metabolite levels	9.000000e-06
GCST009725_65	Intraocular pressure	1.000000e-08
GCST010244_166	Triglyceride levels	4.000000e-11
GCST011347_13	Low density lipoprotein cholesterol levels	5.000000e-14
GCST90020026_440	Hip index	3.000000e-08
GCST90020026_441	Hip index	2.000000e-08
GCST90020026_581	Hip index	1.000000e-09
GCST90020028_17	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_18	Hip circumference adjusted for BMI	4.000000e-08
GCST90020028_439	Hip circumference adjusted for BMI	2.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0007650	soluble interleukin-2 receptor subunit alpha measurement
EFO:0006952	cytotoxicity measurement
EFO:0004831	RR interval
EFO:0007916	response to tricyclic antidepressant
EFO:0004704	age at menopause
EFO:0004695	intraocular pressure measurement
EFO:0003924	hair color
EFO:0004531	urate measurement
EFO:0010411	triacylglycerol 50:4 measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Capzimin	IC50	340 nM	US-10005735: Inhibitors of RPN11

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
8-sulfanyl-N-[2-(1,3-thiazol-2-yl)ethyl]quinoline-3-carboxamide	1802703: In Vitro BRCC36 Activity Assay from Article 10.1038/nchembio.2326: “Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11.”	ic50	2.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	6
Valproic Acid	affects expression, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
biochanin A	increases expression	1
lasiocarpine	increases expression, increases metabolic processing	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
glycidyl methacrylate	decreases expression	1
riddelliine	increases expression, increases metabolic processing	1
zinc chromate	decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
ICG 001	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects expression	1
Cadmium	increases expression	1
Dinitrofluorobenzene	increases expression	1
Estradiol	affects expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression, increases expression	1
Ivermectin	decreases expression	1
Oxazolone	increases expression	1
Rotenone	decreases expression	1
Theophylline	affects cotreatment, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1LH	Abcam HeLa BRE KO	Cancer cell line	Female
CVCL_E1S9	HAP1 BRE (-) 1	Cancer cell line	Male
CVCL_E1SA	HAP1 BRE (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer