CHRNB2

Chr 1AD

cholinergic receptor nicotinic beta 2 subunit

Also known as: EFNL3, nAChRB2

NCBI Gene: 1141 ENSG00000160716 UniProt: P17787 OMIM: 118507

This protein forms the beta-2 subunit of pentameric neuronal acetylcholine receptors, which are ligand-gated cation channels with high calcium permeability that mediate excitatory synaptic transmission in the nervous system. Mutations cause autosomal dominant nocturnal frontal lobe epilepsy, a form of epilepsy characterized by seizures that occur predominantly during sleep. The gene shows tolerance to loss-of-function variants (pLI 0.0007), suggesting the pathogenic variants likely affect receptor function through other mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.821 OMIM phenotype

Clinical Summary— CHRNB2

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Gene-Disease Validity (ClinGen)

familial sleep-related hypermotor epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 378 VUS of 694 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHRNB2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.001

Z-score 2.11

OE 0.46 (0.27–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.10Z-score

OE missense 0.67 (0.60–0.75)

221 obs / 328.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.46 (0.27–0.82)

0≤0.351.4

Missense OE?0.67 (0.60–0.75)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 8 / 17.6Missense obs/exp: 221 / 328.2Syn Z: -0.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCHRNB2-related nocturnal frontal lobe epilepsyGOFAD

This gene — mechanism propensity

0.82top 10%

GOF

0.85top 5%

LOF

0.1993th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

694 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic5

VUS378

Likely Benign260

Benign18

Conflicting29

Pathogenic

Likely Pathogenic

378

VUS

260

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	1	4	0	0	5
VUS	42	321	7	8	378
Likely Benign	0	14	51	195	260
Benign	0	0	17	1	18
Conflicting	—				29
Total	43	341	75	204	692

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap CHRNB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →