GABRA2

Chr 4MultiAD

gamma-aminobutyric acid type A receptor subunit alpha2

Also known as: DEE78, EIEE78

NCBI Gene: 2555 ENSG00000151834 UniProt: P47869 OMIM: 137140

The GABRA2 gene encodes the alpha-2 subunit of GABA-A receptors, which are ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Pathogenic variants cause developmental and epileptic encephalopathy 78 through autosomal dominant inheritance, likely due to disrupted GABAergic inhibition. The gene shows extreme intolerance to loss-of-function variants (pLI 0.996, LOEUF 0.229), consistent with dominant negative or haploinsufficiency mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismMulti/ADLOEUF 0.232 OMIM phenotypes

Clinical Summary— GABRA2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 152 VUS of 370 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.23LOEUF

pLI 0.996

Z-score 4.01

OE 0.05 (0.02–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.13Z-score

OE missense 0.42 (0.36–0.50)

97 obs / 230.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.23)

0≤0.351.4

Missense OE?0.42 (0.36–0.50)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 1 / 20.7Missense obs/exp: 97 / 230.7Syn Z: 0.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGABRA2-related epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.6258th %ile

GOF

0.7127th %ile

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.23

GOFprediction above median · 90% of P/LP are missense

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.

Literature Evidence

LOFAltogether, we identified four heterozygous missense variants in GABRA2 and provided a functional screen that yielded results compatible with a loss of function mechanism.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31032849 ↗

ClinVar Variant Classifications

370 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic14

VUS152

Likely Benign162

Benign18

Conflicting14

Pathogenic

Likely Pathogenic

152

VUS

162

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	4	0	0	6
Likely Pathogenic	0	14	0	0	14
VUS	21	123	6	2	152
Likely Benign	3	35	53	71	162
Benign	0	2	12	4	18
Conflicting	—				14
Total	26	178	71	77	366

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap GABRA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →