GABRB2

Chr 5AD

gamma-aminobutyric acid type A receptor subunit beta2

Also known as: DEE92, ICEE2

NCBI Gene: 2561 ENSG00000145864 UniProt: P47870 OMIM: 600232

The GABA A receptor beta 2 subunit forms part of chloride channels that mediate fast inhibitory synaptic transmission in the central nervous system. Mutations cause developmental and epileptic encephalopathy 92 through an autosomal dominant inheritance pattern via a gain-of-function mechanism. The protein localizes to the postsynaptic cell membrane where it functions as a critical component of GABAergic inhibitory signaling.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.391 OMIM phenotype

Clinical Summary— GABRB2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

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ClinVar Variants

55 unique Pathogenic / Likely Pathogenic· 212 VUS of 596 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.39LOEUF

pLI 0.849

Z-score 3.76

OE 0.17 (0.08–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.40Z-score

OE missense 0.45 (0.39–0.52)

133 obs / 298.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.17 (0.08–0.39)

0≤0.351.4

Missense OE0.45 (0.39–0.52)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 4 / 23.8Missense obs/exp: 133 / 298.0Syn Z: -0.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGABRB2-related epilepsy and intellectual disabilityOTHERAD

0.6841th %ile

GOF

0.74top 25%

LOF

0.4825th %ile

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

DNprediction above median · 1 literature citation

GOFprediction above median · 82% of P/LP are missense

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

DNThis discrepancy suggests that, in addition to compromising subunit protein trafficking, the p.Thr287Pro mutation also functionally impairs the mutant GABAA receptors that do reach the surface. This impaired channel function may be due to a dominant negative effect of p.Thr287Pro mutation in TM2, a PMID:27789573

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