CACNG6

Chr 19

calcium voltage-gated channel auxiliary subunit gamma 6

NCBI Gene: 59285 ENSG00000130433 UniProt: Q8WXS5 OMIM: 606898

This protein regulates L-type calcium channels and AMPA glutamate receptors by modulating their trafficking to synapses and gating properties. The gene is not well-established as a cause of pediatric neurological disease, though variants have been associated with aspirin-intolerant asthma. The gene shows low constraint against loss-of-function variants, suggesting haploinsufficiency is likely tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Voltage-dependent calcium channels are composed of five subunits. The protein encoded by this gene represents one of these subunits, gamma, and is one of two known gamma subunit proteins. This particular gamma subunit is an integral membrane protein that is thought to stabilize the calcium channel in an inactive (closed) state. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family and is located in a cluster with two family members that function as transmembrane AMPA receptor regulatory proteins (TARPs). Alternative splicing results in multiple transcript variants. Variants in this gene have been associated with aspirin-intolerant asthma. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.69

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.69LOEUF

pLI 0.000

Z-score 0.14

OE 0.94 (0.53–1.69)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.32Z-score

OE missense 0.92 (0.79–1.07)

120 obs / 130.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.94 (0.53–1.69)

0≤0.351.4

Missense OE?0.92 (0.79–1.07)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 7 / 7.4Missense obs/exp: 120 / 130.2Syn Z: 0.93

Background carrier burden — how many people carry a rare variant somewhere in CACNG6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

368 rare PASS variants

Rare truncating (LoF)

1 in 660

67 rare PASS variants

Rare synonymous (reference)

1 in 270

194 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CACNG6; this gene does not show strong loss-of-function constraint by this measure. 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 270	1 in 2,200
South Asian	~43k	1 in 140	1 in 1,200
Remaining (unassigned)	~30k	1 in 130	1 in 400
European (Finnish)	~27k	1 in 730	1 in 1,800
Admixed American	~22k	1 in 100	1 in 680
African / African American	~21k	1 in 140	1 in 1,700
East Asian	~20k	1 in 300	≈ 1 in 4,700
Ashkenazi Jewish	~13k	1 in 2,100	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 87	≈ 1 in 1,400

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): 2 of 4 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: all 4.? see exons ↓