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…

MultiplemechanismLOEUF 1.69

Clinical Summary— CACNG6

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

59 VUS of 66 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.69LOEUF

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

This gene — mechanism propensity

0.6551th %ile

GOF

0.6638th %ile

LOF

0.3453th %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.

ClinVar Variant Classifications

66 submitted variants in ClinVar

ClinVar

Classification Summary

VUS59

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	59	59
Likely Benign	1	1
Benign	0	0
Total	60	60

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap CACNG6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →