ADRA2B
protein-codingadrenoceptor alpha 2B, the group of Adrenoceptors
Gene summary
This intronless gene encodes a seven-pass transmembrane protein. This protein is a member of a subfamily of G protein-coupled receptors that regulate neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. [provided by RefSeq, Apr 2014]
- ADRA2L1
- ADRA2RL1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019448
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0011930
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0005027
Submitter: ClinGen
*ADRA2B* was first reported in relation to autosomal dominant familial adult myoclonic epilepsy (FAME2), also called autosomal dominant cortical myoclonus and epilepsy (ADCME) in 2014 (De Fusco et al., PMID: 24114805). This condition is characterized by myoclonic tremor onset in the second to third decade of life, followed by onset of seizures, with considerable phenotypic variability (PMID: 31664034). Originally, in 2001, genome-wide linkage analysis was used to identify a region spanning 2p11.1-q12.2 (PMID: 11701600). In 2014, within that region, an indel in *ADRA2B* was found to segregate with disease in two families (PMID: 24114805). Subsequently (in 2019), a variant in a different gene (intronic ATTTC expansions in *STARD7*) within the linkage region was found to segregate with disease in 158 individuals from 22 families, including the originally reported families (PMID: 31664034). Therefore, the originally reported *ADRA2B* variant was no longer considered to be causative for the families’ epilepsy. No additional variants in *ADRA2B* have been reported in individuals with epilepsy. In summary, the evidence supporting the relationship between *ADRA2B* and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date June 18, 2024 (SOP Version 10).
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
Comments: As with many disorders involving seizures, appropriate interventions may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ADRA2B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000682.7. 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 | 11 | 2 | 13 | |||
| missense | 1 | 46 | 4 | 51 | ||
| nonsense | 1 | 2 | 3 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 2 | 51 | 15 | 2 | 70 |
Highest pathogenic variant AF is 0.0000065695253
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000673.2 | 1 | MANE Select | |
| Ensembl | ENSP00000480573.1 | 1 | MANE Select |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- cGMP-PKG signaling pathway - Homo sapiens (human)
- Sympathetic Nerve Pathway (Neuroeffector Junction)
- GPCRs, Class A Rhodopsin-like
- Monoamine GPCRs
Biological Process
- activation of MAPK activity
- regulation of vascular smooth muscle contraction
- G protein-coupled receptor signaling pathway
- adenylate cyclase-modulating G protein-coupled receptor signaling pathway
- cell-cell signaling
Molecular Function
- adrenergic receptor activity
- alpha2-adrenergic receptor activity
- protein binding
- epinephrine binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- cell surface
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol. {ECO:0000269|PubMed:23105096}.;
- Disease
- DISEASE: Epilepsy, familial adult myoclonic, 2 (FAME2) [MIM:607876]: A form of cortical myoclonic tremor with epilepsy, a syndrome characterized by cortical myoclonus and variable occurrence of epileptic seizures. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom; both complex partial as well as generalized tonic clonic seizures are described. Some patients exhibit mild cognitive impairment. {ECO:0000269|PubMed:24114805}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.111
Intolerance Scores
- LoFtool
- 0.761
- RVIS EVS
- -0.25
- RVIS percentile EVS
- 35.99
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.450
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |