GABRB2
protein-codinggamma-aminobutyric acid type A receptor subunit beta2, the group of Gamma-aminobutyric acid type A receptor subunits
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~260.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020631
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
Variants in *GABRB2* were first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2011 (Kumari et al., PMID 21420396). Individuals with variants in *GABRB2* can present with features such as developmental and epileptic encephalopathy, early-onset epilepsy, various types of seizures, fever sensitivity, developmental delay, intellectual disability, and movement disorders (PMIDs: 27789573, 32686847, 33325057). Sixteen missense variants that have been reported in 20 probands in 5 publications (PMIDs: 25124326, 27789573, 29100083, 32686847, 33325057) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most variants occur *de novo* but may also be inherited from an affected parent. Functional analysis of four missense variants demonstrated that they resulted in loss of function (PMID: 33325057). Pathogenic variants are localized in regions intolerant to functional variation, and cluster in the extracellular N-terminus and transmembrane domains 1–3. No truncating variants or deletions have been identified to date in affected individuals (PMID: 33325057). In summary, there is definitive evidence supporting the relationship between *GABRB2* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 16, 2024 (SOP 10).
Inheritance Pattern: AD
Disease ID:MONDO:0020631
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018614
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020631
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0020631
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GABRB2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001371727.1. 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 | 3 | 135 | 2 | 140 | ||
| missense | 17 | 51 | 198 | 44 | 22 | 332 |
| nonsense | 5 | 1 | 6 | |||
| start loss | 1 | 1 | ||||
| frameshift | 8 | 8 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 1 | 4 | |||
| Total | 17 | 51 | 218 | 181 | 24 | 491 |
Highest pathogenic variant AF is 0.0000025104907
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001358656.1 | 10 | MANE Select | |
| Ensembl | ENSP00000377531.1 | 10 | MANE Select | |
| RefSeq | NP_000804.1 | 9 | Standard | |
| RefSeq | NP_068711.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Benzodiazepine Pathway, Pharmacodynamics
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- GABAergic synapse - Homo sapiens (human)
- Serotonergic synapse - Homo sapiens (human)
- Nicotine addiction - Homo sapiens (human)
Biological Process
- signal transduction
- gamma-aminobutyric acid signaling pathway
- chemical synaptic transmission
- sensory perception of sound
- ion transmembrane transport
Molecular Function
- GABA-A receptor activity
- extracellular ligand-gated ion channel activity
- inhibitory extracellular ligand-gated ion channel activity
- chloride channel activity
- GABA receptor activity
Cellular Component
- cytosol
- plasma membrane
- integral component of plasma membrane
- cell junction
- cytoplasmic vesicle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000274547
- Coding exons
- 10
- Length
- 260615
- Individuals with no LoFs
- 125692
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125695
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.40 | 133 | 298 | 0.446 | 0.0000161 | 3376 |
| Missense (PolyPhen) | 18 | 129.91 | 0.13856 | 1537 | ||
| Synonymous | -0.922 | 121 | 109 | 1.11 | 0.00000563 | 989 |
| Loss of Function | 3.76 | 4 | 23.8 | 0.168 | 0.00000117 | 280 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand- gated chloride channel. {ECO:0000269|PubMed:19763268, ECO:0000269|PubMed:27789573, ECO:0000269|PubMed:8264558}.;
Recessive Scores
- pRec
- 0.156
Intolerance Scores
- LoFtool
- 0.0759
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 14.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.871
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |