GABBR2

protein-coding

gamma-aminobutyric acid type B receptor subunit 2, the group of Gamma-aminobutyric acid type B receptor subunits

Gene summary

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]

Previous symbols:

GPR51

MANE transcript

NM_005458.8

Inheritance

ClinVar variants

P:17U:394B:407

Top phenotype

Epileptic encephalopathy, early infantile, 59; Neurodevelopmental disorder with poor language and loss of hand skills

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr9:98,288,109-98,708,935

External References & Databases

Ensembl (ENSG00000136928)

Transcript & Mutation Effects

hg38 • Region Span ~420.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 59STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033368

Submitter: G2P

developmental and epileptic encephalopathy, 59MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033368

Submitter: Ambry Genetics

neurodevelopmental disorder with poor language and loss of hand skillsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060659

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*GABBR2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder (CND) in 2014 by EuroEPINOMICS-RES Consortium (PMID: 25262651), reporting individuals with seizures, severe intellectual disability, developmental delay, speech delay and autistic features. The current literature displays a broad range of phenotypes for patients with variants in *GABBR2*. Some probands with heterozygous variants have been reported with drooling, hypotonia, and scoliosis in addition to seizures (PMID: 29100083). Other probands have been reported with neurodevelopmental disorder with poor language and loss of hand skills (Atypical RTT) (PMID: 28856709, 29369404) with or without seizures (PMID: 26740508, 28856709, 29369404). Given the broad neurodevelopmental phenotypes present in these individuals, we have chosen to curate this gene-disease relationship under the disease term complex neurodevelopmental disorder (CND) (MONDO:0100038). Five missense variants reported in nine probands across five publications were included in this curation (PMIDs: 25262651, 29100083, 26740508); several of these variants were supported by functional evidence (PMID: 28856709, 29369404). Of note, one individual with a mosaic heterozygous missense variant in *GABBR2* was scored, due to the presence of functional data demonstrating an impact on the protein (PMID: 25262651, 28856709, 29369404). In summary, there is moderate evidence to support the relationship between *GABBR2* and autosomal dominant complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on November 19, 2024 (SOP version 11).

neurodevelopmental disorder with poor language and loss of hand skillsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060659

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 59STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033368

Submitter: Labcorp Genetics (formerly Invitae)

atypical Rett syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017746

Submitter: Orphanet

Clinical Genomic Database (CGD)

Epileptic encephalopathy, early infantile, 59; Neurodevelopmental disorder with poor language and loss of hand skillsAD

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25262651; 26740508; 28856709; 29100083; 29369404

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GABBR2 variants in ClinVar

12 Conditions Cataloged

Epileptic encephalopathyTotal: 898

not providedTotal: 217

Inborn genetic diseasesTotal: 63

Developmental and epileptic encephalopathy, 59Total: 34

GABBR2-related disorderTotal: 23

Neurodevelopmental disorder with poor language and loss of hand skillsTotal: 20

not specifiedTotal: 17

Intellectual disabilityTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005458.8. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	287 clinvar	11 clinvar	305
missense	5 clinvar	10 clinvar	358 clinvar	92 clinvar	13 clinvar	478
nonsense		1 clinvar	8 clinvar	1 clinvar		10
start loss						0
frameshift		1 clinvar	11 clinvar	1 clinvar		13
splice donor/acceptor (+/-2bp)			10 clinvar	2 clinvar		12
Total	5	12	394	383	24	818

Highest pathogenic variant AF is 0.0000012632212

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005458.8	RefSeq	NP_005449.5	19	MANE Select
ENST00000259455.4	Ensembl	ENSP00000259455.2	19	MANE Select
ENST00000634457.1	Ensembl	ENSP00000489352.1	4	Standard
ENST00000637717.1	Ensembl	ENSP00000490789.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GABAergic synapse - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)
Estrogen signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Taste transduction - Homo sapiens (human)

Biological Process

G protein-coupled receptor signaling pathway
negative regulation of adenylate cyclase activity
gamma-aminobutyric acid signaling pathway
chemical synaptic transmission

Molecular Function

G protein-coupled GABA receptor activity
protein binding
protein heterodimerization activity

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
cell junction
G protein-coupled receptor heterodimeric complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259455
Coding exons: 19
Length: 421089
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.63	236	538	0.439	0.0000320	6161
Missense (PolyPhen)		48	164.64	0.29155		1807
Synonymous	0.279	215	220	0.976	0.0000147	1853
Loss of Function	5.91	3	46.4	0.0646	0.00000239	513

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10075644, PubMed:10773016, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644, PubMed:9872744, PubMed:10906333, PubMed:10773016). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872744, PubMed:22660477). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:9872316, PubMed:10075644, PubMed:9872744, PubMed:22660477). Not only implicated in synaptic inhibition but also in hippocampal long- term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable). {ECO:0000269|PubMed:10075644, ECO:0000269|PubMed:10328880, ECO:0000269|PubMed:15617512, ECO:0000269|PubMed:18165688, ECO:0000269|PubMed:22660477, ECO:0000269|PubMed:24305054, ECO:0000269|PubMed:9872316, ECO:0000269|PubMed:9872744, ECO:0000305}.;
Disease: DISEASE: Neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) [MIM:617903]: An autosomal dominant disorder characterized by psychomotor developmental stagnation or regression. NDPLHS manifest in the first years of life as loss of purposeful hand movements, loss of language, and intellectual disability. {ECO:0000269|PubMed:26740508, ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29369404}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 59 (EIEE59) [MIM:617904]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE59 is an autosomal dominant condition characterized by onset of refractory seizures in early infancy. {ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29100083, ECO:0000269|PubMed:29369404}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.138
RVIS EVS: -1.29
RVIS percentile EVS: 5.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.618

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium