ANO3

Chr 11AD

anoctamin 3

Also known as: C11orf25, DYT23, DYT24, GENX-3947, TMEM16C

NCBI Gene: 63982 ENSG00000134343 UniProt: Q9BYT9 OMIM: 610110

The protein is a transmembrane calcium-activated chloride channel that belongs to the anoctamin family and modulates calcium signaling pathways. Mutations cause autosomal dominant craniocervical dystonia (dystonia 24) through a gain-of-function mechanism that disrupts endoplasmic reticulum-dependent calcium signaling. The inheritance pattern is autosomal dominant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the TMEM16 family of predicted membrane proteins, that are also known as anoctamins. While little is known about the function of this gene, mutations in this gene have been associated with some cases of autosomal dominant craniocervical dystonia. Cells from individuals with a mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling. Studies in rat show that the rat ortholog of this protein interacts with, and modulates the activity of a sodium-activated potassium channel. Deletion of this gene caused increased pain sensitivity in the rat model system. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.771 OMIM phenotype

Clinical Summary— ANO3

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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

12 unique Pathogenic / Likely Pathogenic· 337 VUS of 715 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ANO3

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 3.11

OE 0.58 (0.45–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.46Z-score

OE missense 0.70 (0.65–0.76)

378 obs / 538.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.58 (0.45–0.77)

0≤0.351.4

Missense OE?0.70 (0.65–0.76)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 38 / 65.0Missense obs/exp: 378 / 538.4Syn Z: -0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongANO3-related dystoniaOTHERAD

This gene — mechanism propensity

0.80top 25%

GOF

0.79top 25%

LOF

0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 100% of P/LP are missense

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

715 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic6

VUS337

Likely Benign205

Benign134

Conflicting14

Pathogenic

Likely Pathogenic

337

VUS

205

Likely Benign

134

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	6	0	0	6
Likely Pathogenic	0	6	0	0	6
VUS	29	280	20	8	337
Likely Benign	1	12	111	81	205
Benign	0	4	118	12	134
Conflicting	—				14
Total	30	308	249	101	702

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap ANO3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →