GABRA6

Chr 5

gamma-aminobutyric acid type A receptor subunit alpha6

NCBI Gene: 2559 ENSG00000145863 UniProt: Q16445 OMIM: 137143

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.38

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.38LOEUF

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

Background carrier burden — how many people carry a rare variant somewhere in GABRA6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

694 rare PASS variants

Rare truncating (LoF)

1 in 1,100

115 rare PASS variants

Rare synonymous (reference)

1 in 160

245 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GABRA6. 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 170	1 in 1,200
South Asian	~43k	1 in 97	1 in 360
Remaining (unassigned)	~30k	1 in 110	1 in 1,900
European (Finnish)	~27k	1 in 340	1 in 990
Admixed American	~22k	1 in 70	1 in 650
African / African American	~21k	1 in 85	1 in 390
East Asian	~20k	1 in 80	1 in 1,400
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 85	≈ 1 in 580

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 ↓