DOC2A

Chr 16

double C2 domain alpha

Also known as: Doc2

NCBI Gene: 8448 ENSG00000149927 UniProt: Q14183 OMIM: 604567

DOC2A encodes a calcium sensor protein that regulates calcium-dependent neurotransmitter release by controlling vesicle fusion with membranes in neurons. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe seizures, developmental delay, and progressive neurodegeneration. The gene shows moderate constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

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. DOC2A is mainly expressed in brain and is suggested to be involved in Ca(2+)-dependent neurotransmitter release. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.69

Clinical Summary— DOC2A

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — 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?

0.69LOEUF

pLI 0.007

Z-score 2.56

OE 0.37 (0.21–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.09Z-score

OE missense 0.81 (0.72–0.91)

210 obs / 259.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.21–0.69)

0≤0.351.4

Missense OE?0.81 (0.72–0.91)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 7 / 19.1Missense obs/exp: 210 / 259.3Syn Z: -0.08

This gene — mechanism propensity

0.7325th %ile

GOF

0.80top 10%

LOF

0.3746th %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.