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

The multi-pass membrane protein encoded by this gene belongs to the G-protein coupled receptor 3 family and GABA-B receptor subfamily. The GABA-B receptors inhibit neuronal activity through G protein-coupled second-messenger systems, which regulate the release of neurotransmitters, and the activity of ion channels and adenylyl cyclase. This receptor subunit forms an active heterodimeric complex with GABA-B receptor subunit 1, neither of which is effective on its own. Allelic variants of this gene have been associated with nicotine dependence.[provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 426 VUS of 1167 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?

0.17LOEUF

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 OE?0.06 (0.03–0.17)

0≤0.351.4

Missense OE?0.44 (0.39–0.49)

0≤0.61.4

Synonymous OE?0.98

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

This gene — mechanism propensity

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 · 88% of P/LP are missense

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.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 28856709 ↗

ClinVar Variant Classifications

1167 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic12

VUS426

Likely Benign540

Benign142

Conflicting35

Pathogenic

Likely Pathogenic

426

VUS

540

Likely Benign

142

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	1	10	1	0	12
VUS	27	370	23	6	426
Likely Benign	2	65	188	285	540
Benign	0	14	113	15	142
Conflicting	—				35
Total	30	464	325	306	1,160

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap GABBR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →