BIN1

Chr 2AR

bridging integrator 1

Also known as: AMPH2, AMPHL, CNM2, SH3P9

NCBI Gene: 274 ENSG00000136717 UniProt: O00499 OMIM: 601248

The protein functions as a nucleocytoplasmic adaptor involved in synaptic vesicle endocytosis in the central nervous system and localizes to muscle cytoplasm and nucleus where it can activate apoptotic processes. Mutations cause centronuclear myopathy 2, inherited in an autosomal recessive pattern. The high constraint scores (pLI 0.78, LOEUF 0.37) indicate the gene is intolerant to loss-of-function variants, consistent with pathogenicity through loss of normal protein function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.371 OMIM phenotype

Clinical Summary— BIN1

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Gene-Disease Validity (ClinGen)

centronuclear myopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 375 VUS of 850 total submissions

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GeneReview available — BIN1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.778

Z-score 4.46

OE 0.20 (0.11–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.25Z-score

OE missense 0.66 (0.60–0.74)

235 obs / 354.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.20 (0.11–0.37)

0≤0.351.4

Missense OE?0.66 (0.60–0.74)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 7 / 35.8Missense obs/exp: 235 / 354.2Syn Z: 0.26

ClinVar Variant Classifications

850 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic5

VUS375

Likely Benign328

Benign77

Conflicting44

Pathogenic

Likely Pathogenic

375

VUS

328

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	3	2	0	0	5
VUS	18	292	58	7	375
Likely Benign	0	7	191	130	328
Benign	0	1	75	1	77
Conflicting	—				44
Total	22	304	324	138	832

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap BIN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →