BIN1

Chr 2

bridging integrator 1

Also known as: AMPH2, AMPHL, CNM2, SH3P9

NCBI Gene: 274 ENSG00000136717 UniProt: O00499

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]

Primary Disease Associations & Inheritance

UniProtMyopathy, centronuclear, 2

662

ClinVar variants

Pathogenic / LP

0.78

pLI score

Active trials

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

20 Pathogenic / Likely Pathogenic· 286 VUS of 662 total submissions

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.11–0.37)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.60–0.74)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97

0≤1.21.6

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