GABBR2

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

Basic information

Region (hg38): 9:98288109-98708935

Previous symbols: [ "GPR51" ]

Links

ENSG00000136928 ∙ NCBI:9568 ∙ OMIM:607340 ∙ HGNC:4507 ∙ Uniprot:O75899 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 59 (Moderate), mode of inheritance: AD
• atypical Rett syndrome (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 59 (Strong), mode of inheritance: AD
• neurodevelopmental disorder with poor language and loss of hand skills (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epileptic encephalopathy, early infantile, 59; Neurodevelopmental disorder with poor language and loss of hand skills	AD	General	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	Musculoskeletal; Neurologic	25262651; 26740508; 28856709; 29100083; 29369404

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GABBR2 gene.

• Epileptic encephalopathy (2 variants)
• not provided (1 variants)
• Rett syndrome (1 variants)
• Neurodevelopmental disorder with poor language and loss of hand skills (1 variants)
• GABBR2-related disorder (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GABBR2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	231	14	251
missense	2	7	249	65	14	337
nonsense		1	5	1		7
start loss						0
frameshift			6			6
inframe indel			12	4		16
splice donor/acceptor (+/-2bp)			3			3
splice region			14	43	8	65
non coding			1	125	103	229
Total	2	8	282	426	131

Variants in GABBR2

This is a list of pathogenic ClinVar variants found in the GABBR2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-98288678-A-G		Neurodevelopmental disorder with poor language and loss of hand skills;Developmental and epileptic encephalopathy, 59	Uncertain significance (Apr 23, 2021)
9-98290274-T-G			Benign (Aug 21, 2019)
9-98290275-T-TC			Likely benign (Sep 02, 2019)
9-98290276-T-G			Likely benign (Aug 06, 2019)
9-98290277-T-G			Benign (Aug 20, 2019)
9-98290279-T-G			Benign (Aug 21, 2019)
9-98290280-T-TG			Benign (Aug 06, 2019)
9-98290281-T-TG			Benign (Aug 04, 2021)
9-98290284-T-G			Benign (Aug 06, 2019)
9-98290284-T-TG			Benign (Aug 20, 2019)
9-98290576-T-C			Benign (Jul 15, 2018)
9-98290577-C-T		GABBR2-related disorder	Benign (May 11, 2021)
9-98290582-C-T			Likely benign (Jan 14, 2020)
9-98290587-C-T		Epileptic encephalopathy	Likely benign (Oct 12, 2021)
9-98290593-C-G		Epileptic encephalopathy	Likely benign (Oct 30, 2023)
9-98290593-C-T		Epileptic encephalopathy	Likely benign (Mar 23, 2022)
9-98290606-C-T		Epileptic encephalopathy	Uncertain significance (Sep 09, 2023)
9-98290607-G-A		Epileptic encephalopathy	Uncertain significance (Oct 11, 2021)
9-98290610-A-G		Epileptic encephalopathy	Uncertain significance (Jul 11, 2022)
9-98290622-C-T		GABBR2-related disorder	Uncertain significance (May 17, 2024)
9-98290623-A-T			Uncertain significance (Sep 23, 2023)
9-98290624-T-C		Epileptic encephalopathy	Likely benign (Oct 16, 2023)
9-98290631-G-GGCGGGGGCTGGCGGTGGGGCTGAC		Epileptic encephalopathy	Uncertain significance (Jan 11, 2024)
9-98290633-C-G		Epileptic encephalopathy	Likely benign (Feb 02, 2022)
9-98290633-C-T		Inborn genetic diseases • Developmental and epileptic encephalopathy, 59 • Epileptic encephalopathy	Uncertain significance (Mar 29, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GABBR2	protein_coding	protein_coding	ENST00000259455	19	421089

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000719	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.63	236	538	0.439	0.0000320	6161
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000362	0.0000352
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Morphine addiction - Homo sapiens (human);Splicing factor NOVA regulated synaptic proteins;GPCRs, Class C Metabotropic glutamate, pheromone;Signaling by GPCR;Signal Transduction;Neuronal System;Class C/3 (Metabotropic glutamate/pheromone receptors);GPCR ligand binding;Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits;Activation of GABAB receptors;GABA B receptor activation;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;G alpha (i) signalling events;Activation of G protein gated Potassium channels;GPCR downstream signalling;G protein gated Potassium channels;Inwardly rectifying K+ channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.156

Intolerance Scores

• loftool: 0.138
• rvis_EVS: -1.29
• rvis_percentile_EVS: 5.08

Haploinsufficiency Scores

• pHI: 0.721
• hipred: Y
• hipred_score: 0.809
• ghis: 0.639

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.618

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gabbr2
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: G protein-coupled receptor signaling pathway;negative regulation of adenylate cyclase activity;gamma-aminobutyric acid signaling pathway;chemical synaptic transmission
• Cellular component: cytoplasm;plasma membrane;integral component of plasma membrane;cell junction;G protein-coupled receptor heterodimeric complex;neuron projection;postsynaptic membrane;GABA receptor complex
• Molecular function: G protein-coupled GABA receptor activity;protein binding;protein heterodimerization activity