CHRNA6

Chr 8

cholinergic receptor nicotinic alpha 6 subunit

Also known as: CHNRA6

NCBI Gene: 8973 ENSG00000147434 UniProt: Q15825

The protein forms a subunit of pentameric neuronal nicotinic acetylcholine receptors that function as ligand-gated cation channels with high calcium permeability, mediating cholinergic modulation of dopamine and GABA release in specific brain regions including dopaminergic and norepinephrine neurons. Mutations cause autosomal dominant nocturnal frontal lobe epilepsy, a sleep-related seizure disorder typically beginning in childhood or adolescence. The gene shows very high constraint against loss-of-function variants (pLI near 1), indicating that complete loss of function is likely incompatible with normal development.

GeneReviews ResearchSummary from RefSeq, UniProt

This gene encodes an alpha subunit of neuronal nicotinic acetylcholine receptors. These receptors consist of five subunits and function as ion channels involved in neurotransmission. The encoded protein is a subunit of neuronal nicotinic acetylcholine receptors that mediate dopaminergic neurotransmission and are activated by acetylcholine and exogenous nicotine. Alternatively spliced transcript variants have been observed for this gene. Single nucleotide polymorphisms in this gene have been associated with both nicotine and alcohol dependence. [provided by RefSeq, Dec 2010]

GeneReviews ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — CHRNA6

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 1.06

OE 0.74 (0.49–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.12Z-score

OE missense 0.98 (0.88–1.08)

262 obs / 267.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.49–1.15)

0≤0.351.4

Missense OE?0.98 (0.88–1.08)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 14 / 19.0Missense obs/exp: 262 / 267.8Syn Z: 0.57

Background carrier burden — how many people carry a rare variant somewhere in CHRNA6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 79

588 rare PASS variants

Rare truncating (LoF)

1 in 400

96 rare PASS variants

Rare synonymous (reference)

1 in 180

238 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CHRNA6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 1,500
South Asian	~43k	1 in 86	1 in 820
Remaining (unassigned)	~30k	1 in 61	1 in 500
European (Finnish)	~27k	1 in 240	1 in 490
Admixed American	~22k	1 in 88	1 in 930
African / African American	~21k	1 in 83	1 in 920
East Asian	~20k	1 in 150	1 in 1,200
Ashkenazi Jewish	~13k	1 in 790	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 130	≈ 1 in 950

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.