DOC2B

Chr 17

double C2 domain beta

Also known as: DOC2BL

NCBI Gene: 8447 ENSG00000272636 UniProt: Q14184 OMIM: 604568

DOC2B encodes a calcium sensor protein that regulates SNARE-dependent vesicle fusion with membranes and is involved in neurotransmitter release and insulin secretion. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe seizures, developmental delay, and movement disorders. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

There are at least two protein isoforms of the Double C2 protein, namely alpha (DOC2A) and beta (DOC2B), which contain two C2-like domains. DOC2A and DOC2B are encoded by different genes; these genes are at times confused with the unrelated DAB2 gene which was initially named DOC-2. DOC2B is expressed ubiquitously and is suggested to be involved in Ca(2+)-dependent intracellular vesicle trafficking in various types of cells. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.06

Clinical Summary— DOC2B

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.017

Z-score 1.45

OE 0.47 (0.23–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.67Z-score

OE missense 0.58 (0.47–0.70)

71 obs / 123.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.23–1.06)

0≤0.351.4

Missense OE?0.58 (0.47–0.70)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 4 / 8.6Missense obs/exp: 71 / 123.3Syn Z: -0.06

This gene — mechanism propensity

0.74top 25%

GOF

0.78top 25%

LOF

0.3939th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.