TBC1D10C

Chr 11

TBC1 domain family member 10C

Also known as: CARABIN, EPI64C

NCBI Gene: 374403 ENSG00000175463 UniProt: Q8IV04 OMIM: 610831

The protein functions as a GTPase-activating protein that inhibits Ras signaling and acts as a negative feedback inhibitor of the calcineurin signaling pathway. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, characterized by early-onset seizures, severe developmental delay, and progressive microcephaly. The gene shows moderate constraint against loss-of-function variants, consistent with the severe neurodevelopmental phenotype observed in affected individuals.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene has an N-terminal Rab-GTPase domain and a binding site at the C-terminus for calcineurin, and is an inhibitor of both the Ras signaling pathway and calcineurin, a phosphatase regulated by calcium and calmodulin. Genes encoding similar proteins are located on chromosomes 16 and 22. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.154

Z-score 3.34

OE 0.26 (0.14–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.92Z-score

OE missense 0.85 (0.76–0.94)

237 obs / 280.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.51)

0≤0.351.4

Missense OE?0.85 (0.76–0.94)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 6 / 23.4Missense obs/exp: 237 / 280.4Syn Z: -0.21

Background carrier burden — how many people carry a rare variant somewhere in TBC1D10C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

675 rare PASS variants

Rare truncating (LoF)

1 in 730

121 rare PASS variants

Rare synonymous (reference)

1 in 180

187 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBC1D10C. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 78	1 in 720
South Asian	~43k	1 in 61	1 in 1,900
Remaining (unassigned)	~30k	1 in 62	1 in 740
European (Finnish)	~27k	1 in 230	1 in 550
Admixed American	~22k	1 in 69	1 in 1,100
African / African American	~21k	1 in 68	1 in 1,000
East Asian	~20k	1 in 59	1 in 1,600
Ashkenazi Jewish	~13k	1 in 270	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 92	1 in 560

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓