GABBR2

Chr 9AD

gamma-aminobutyric acid type B receptor subunit 2

Also known as: DEE59, EIEE59, GABABR2, GPR51, GPRC3B, HG20, HRIHFB2099, NDPLHS

NCBI Gene: 9568 ENSG00000136928 UniProt: O75899 OMIM: 607340

GABBR2 encodes a subunit of the heterodimeric GABA-B receptor that inhibits neuronal activity by modulating neurotransmitter release and ion channel activity, with the GABBR2 subunit specifically mediating G-protein coupling. Mutations cause autosomal dominant developmental and epileptic encephalopathy and neurodevelopmental disorder with poor language and loss of hand skills. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.167), reflecting its critical role in inhibitory synaptic transmission.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.174 OMIM phenotypes

Clinical Summary— GABBR2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADModerate

Moderate evidence — consider for supplementary testing

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.17LOEUF

pLI 1.000

Z-score 5.91

OE 0.06 (0.03–0.17)

Highly constrained

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

Missense Constraint

4.63Z-score

OE missense 0.44 (0.39–0.49)

236 obs / 537.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.06 (0.03–0.17)

0≤0.351.4

Missense OE0.44 (0.39–0.49)

0≤0.61.4

Synonymous OE0.98

0≤1.21.6

LoF obs/exp: 3 / 46.4Missense obs/exp: 236 / 537.9Syn Z: 0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGABBR2-related epileptic encephalopathyOTHERAD

0.4686th %ile

GOF

0.6345th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.17

GOFprediction above median

DN1 literature citation

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

DNIn vitro functional expression studies in HEK293 cells showed that the A567T mutation significantly lowered agonist-induced activity (about 30% of wildtype), suggesting that the mutation exerts a hypomorphic effect through a dominant-negative mechanism.PMID:28856709

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