GABRB2

Chr 5

gamma-aminobutyric acid type A receptor subunit beta2

Also known as: DEE92, ICEE2

NCBI Gene: 2561 ENSG00000145864 UniProt: P47870

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.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.39

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

60 unique Pathogenic / Likely Pathogenic· 218 VUS of 635 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 →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.17 (0.08–0.39)

0≤0.351.4

Missense OE?0.45 (0.39–0.52)

0≤0.61.4

Synonymous OE?1.11

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

This gene — mechanism propensity

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 · 98% 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 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 27789573 ↗

ClinVar Variant Classifications

635 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic42

VUS218

Likely Benign261

Benign65

Conflicting22

Pathogenic

Likely Pathogenic

218

VUS

261

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	17	1	0	18
Likely Pathogenic	0	42	0	0	42
VUS	12	189	14	3	218
Likely Benign	2	29	100	130	261
Benign	0	22	37	6	65
Conflicting	—				22
Total	14	299	152	139	626

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap GABRB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →