GABRP

Chr 5

gamma-aminobutyric acid type A receptor subunit pi

NCBI Gene: 2568 ENSG00000094755 UniProt: O00591

The pi subunit forms part of GABA-A receptors, heteropentameric chloride channels that mediate inhibitory neurotransmission and are expressed in both neuronal and peripheral tissues including uterus and lungs. Mutations cause autosomal recessive early infantile epileptic encephalopathy, characterized by seizure onset in infancy and developmental impairment. This gene shows very low constraint against loss-of-function variants.

ResearchSummary from RefSeq, UniProt

The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. The subunit encoded by this gene is expressed in several non-neuronal tissues including the uterus and ovaries. This subunit can assemble with known GABA A receptor subunits, and the presence of this subunit alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.41

LOEUF

Multiple*

Mechanism· predicted

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?

1.41LOEUF

pLI 0.000

Z-score 0.14

OE 0.97 (0.68–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.16Z-score

OE missense 0.97 (0.87–1.08)

242 obs / 249.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.97 (0.68–1.41)

0≤0.351.4

Missense OE?0.97 (0.87–1.08)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 20 / 20.7Missense obs/exp: 242 / 249.3Syn Z: -0.99

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 87

577 rare PASS variants

Rare truncating (LoF)

1 in 1,700

104 rare PASS variants

Rare synonymous (reference)

1 in 180

230 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GABRP. 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 120	1 in 1,800
South Asian	~43k	1 in 80	1 in 1,300
Remaining (unassigned)	~30k	1 in 69	1 in 1,600
European (Finnish)	~27k	1 in 420	≈ 1 in 13,000
Admixed American	~22k	1 in 99	1 in 470
African / African American	~21k	1 in 85	1 in 1,400
East Asian	~20k	1 in 73	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 320	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 110	≈ 1 in 720

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): 9 of 9 coding exons well covered in gnomAD exomes. Genomes: 8 of 9 (exon 4 below).? see exons ↓