CHRNA7

Chr 15

cholinergic receptor nicotinic alpha 7 subunit

Also known as: CHRNA7-2, NACHRA7, a7nAChR, nAChR7

NCBI Gene: 1139 ENSG00000175344 UniProt: P36544 OMIM: 118511

The protein forms homopentameric nicotinic acetylcholine receptors that function as ligand-gated calcium-permeable ion channels mediating synaptic transmission in the central nervous system, and also plays roles in cholinergic anti-inflammatory signaling in immune cells. Mutations cause autosomal dominant nocturnal frontal lobe epilepsy and are associated with benign familial neonatal-infantile seizures, typically presenting in infancy or childhood. This gene is not highly constrained against loss-of-function variants and has a GeneReviews entry available for detailed clinical guidance.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.77

Clinical Summary— CHRNA7

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Gene-Disease Validity (ClinGen)

epilepsy · UDRefuted

Refuted — evidence has disproved this relationship

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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

1 unique Pathogenic / Likely Pathogenic· 82 VUS of 141 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHRNA7

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?

0.77LOEUF

pLI 0.000

Z-score 2.34

OE 0.44 (0.26–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.25Z-score

OE missense 0.78 (0.69–0.88)

190 obs / 245.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.26–0.77)

0≤0.351.4

Missense OE?0.78 (0.69–0.88)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 9 / 20.4Missense obs/exp: 190 / 245.0Syn Z: 0.71

This gene — mechanism propensity

0.88top 5%

GOF

0.86top 5%

LOF

0.1697th %ile

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

DNprediction above median

GOFprediction 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

141 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS82

Likely Benign26

Benign26

Conflicting2

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	2	75	5	0	82
Likely Benign	0	2	9	15	26
Benign	0	1	22	3	26
Conflicting	—				2
Total	2	78	37	18	137

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

View in ClinVar →

204 pathogenic / likely-pathogenic (of 316) ClinVar copy-number / structural variants overlap CHRNA7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →