GABRA6

Chr 5

gamma-aminobutyric acid type A receptor subunit alpha6

NCBI Gene: 2559 ENSG00000145863 UniProt: Q16445

The GABRA6 protein is an alpha subunit of GABA-A receptors, heteropentameric ligand-gated chloride channels that mediate the major inhibitory neurotransmission in the brain and are found at both synaptic and extrasynaptic sites including glutamatergic synapses. Mutations in GABRA6 cause autosomal recessive early infantile epileptic encephalopathy with febrile seizures plus, characterized by seizure onset in infancy. This gene is not highly constrained against loss-of-function variation, which is consistent with the recessive inheritance pattern observed in associated disorders.

ResearchSummary from RefSeq, UniProt

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.38

Clinical Summary— GABRA6

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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

2 unique Pathogenic / Likely Pathogenic· 52 VUS of 85 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.38LOEUF

pLI 0.000

Z-score 0.25

OE 0.94 (0.65–1.38)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.41Z-score

OE missense 1.07 (0.97–1.19)

257 obs / 239.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.94 (0.65–1.38)

0≤0.351.4

Missense OE?1.07 (0.97–1.19)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 19 / 20.2Missense obs/exp: 257 / 239.2Syn Z: -1.47

This gene — mechanism propensity

0.77top 25%

GOF

0.80top 10%

LOF

0.3066th %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

85 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS52

Likely Benign19

Benign12

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	2	0	2
Likely Pathogenic	0	0	0	0	0
VUS	3	45	4	0	52
Likely Benign	0	8	1	10	19
Benign	0	3	2	7	12
Total	3	56	9	17	85

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap GABRA6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →