CHRNE

Chr 17ADAR

cholinergic receptor nicotinic epsilon subunit

Also known as: ACHRE, CMS1A1, CMS1D, CMS1E, CMS2A, CMS4A, CMS4B, CMS4C

NCBI Gene: 1145 ENSG00000108556 UniProt: Q04844 OMIM: 100725

The epsilon subunit is a component of the pentameric acetylcholine receptor at the neuromuscular junction that replaces the embryonic gamma subunit after birth. Mutations cause congenital myasthenic syndrome through gain-of-function (slow-channel), loss-of-function (fast-channel), or receptor deficiency mechanisms. Inheritance is autosomal dominant for slow-channel forms and autosomal recessive for fast-channel and deficiency forms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.993 OMIM phenotypes

Clinical Summary— CHRNE

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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

54 unique Pathogenic / Likely Pathogenic· 127 VUS of 293 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHRNE

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?

0.99LOEUF

pLI 0.000

Z-score 1.60

OE 0.66 (0.45–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.85Z-score

OE missense 1.13 (1.04–1.24)

359 obs / 316.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.66 (0.45–0.99)

0≤0.351.4

Missense OE?1.13 (1.04–1.24)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 17 / 25.8Missense obs/exp: 359 / 316.4Syn Z: -2.92

This gene — mechanism propensity

0.76top 25%

GOF

0.86top 5%

LOF

0.2093th %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

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic40

VUS127

Likely Benign100

Conflicting1

Pathogenic

Likely Pathogenic

127

VUS

100

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	0	3	0	14
Likely Pathogenic	28	10	2	0	40
VUS	0	106	15	6	127
Likely Benign	0	1	66	33	100
Benign	0	0	0	0	0
Conflicting	—				1
Total	39	117	86	39	282

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 7) ClinVar copy-number / structural variants overlap CHRNE — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →