CHRNB2
protein-codingcholinergic receptor nicotinic beta 2 subunit, the group of Cholinergic receptors nicotinic subunits
Gene summary
Neuronal acetylcholine receptors are homo- or heteropentameric complexes composed of homologous alpha and beta subunits. They belong to a superfamily of ligand-gated ion channels which allow the flow of sodium and potassium across the plasma membrane in response to ligands such as acetylcholine and nicotine. This gene encodes one of several beta subunits. Mutations in this gene are associated with autosomal dominant nocturnal frontal lobe epilepsy. [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 ~12.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020300
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011545
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0000030
Submitter: ClinGen
CHRNB2 was first reported in relation to autosomal dominant sleep-related hypermotor epilepsy in 2000 (De Fusco et al., PMID: 11062464). This disorder was previously referred to as nocturnal frontal lobe epilpeys. It is characterized by hypermotor seizures that occur most often in sleep and are occassionally associated with intellectual disability or psychiatric disorders. At least 8 missense variants that have been reported in 12 probands in 10 publications (PMIDs: 27054081, 33391346, 35177946, 21497487, 18534914, 18456869, 17900292, 15964197, 11104662, 11062464) are included in this curation. The mechanism of pathogenicity appears to be gain-of-function. This gene-disease association is also supported by experimental evidence, including spontaneous seizures during sleep in a rat model and a mouse model, as well as protein-protein interactions with CHRNA4 to form functional nicotinic acetylcholine receptor (nAChR) channels (PMIDs: 26091610, 19153075, 12944511). In summary, there is a definitive relationship between CHRNB2 and autosomal dominant sleep-related hypermotor epilepsy. 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 Epilepsy Gene Curation Expert Panel on February 7th, 2023. As of May 5th, 2023, this record underwent administrative updates in which the disease term in the evidence summary was revised to align with the updated Mondo disease term. No new evidence has been reviewed or added.
Inheritance Pattern: AD
Disease ID:MONDO:0011545
Submitter: G2P
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 the attacks had been interpreted in some instances as being nightmares/sleep walking, a genetic diagnosis may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CHRNB2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000748.3. 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 | 200 | 2 | 209 | ||
| missense | 2 | 5 | 326 | 34 | 1 | 368 |
| nonsense | 14 | 14 | ||||
| start loss | 3 | 3 | ||||
| frameshift | 27 | 27 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 6 | |||
| Total | 2 | 6 | 382 | 234 | 3 | 627 |
Highest pathogenic variant AF is 0.0000074349996
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000739.1 | 6 | MANE Select | |
| Ensembl | ENSP00000357461.3 | 6 | MANE Select | |
| Ensembl | ENSP00000489703.1 | 7 | Standard | |
| Ensembl | ENSP00000490474.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Nicotine addiction - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- Cholinergic synapse - Homo sapiens (human)
- Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
- Levomethadyl Acetate Action Action Pathway
Biological Process
- action potential
- conditioned taste aversion
- response to hypoxia
- ion transport
- calcium ion transport
Molecular Function
- extracellular ligand-gated ion channel activity
- protein binding
- ligand-gated ion channel activity
- acetylcholine receptor activity
- acetylcholine-gated cation-selective channel activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- acetylcholine-gated channel complex
- external side of plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000368476
- Coding exons
- 6
- Length
- 12246
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125748
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.10 | 221 | 328 | 0.673 | 0.0000242 | 3226 |
| Missense (PolyPhen) | 91 | 150.31 | 0.60541 | 1596 | ||
| Synonymous | -0.196 | 148 | 145 | 1.02 | 0.0000118 | 1024 |
| Loss of Function | 2.11 | 8 | 17.6 | 0.456 | 8.68e-7 | 187 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodiun ions. {ECO:0000269|PubMed:22361591}.;
- Disease
- DISEASE: Epilepsy, nocturnal frontal lobe, 3 (ENFL3) [MIM:605375]: An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. {ECO:0000269|PubMed:11062464, ECO:0000269|PubMed:11104662}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.278
Intolerance Scores
- LoFtool
- 0.0740
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 14.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.447
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |