ANO5

Chr 11

anoctamin 5

Also known as: GDD1, LGMD2L, LGMDR12, TMEM16E

NCBI Gene: 203859 ENSG00000171714 UniProt: Q75V66

The protein functions in plasma membrane repair through interaction with annexins and localizes to the endoplasmic reticulum membrane. Mutations cause autosomal recessive limb-girdle muscular dystrophy type 12 and Miyoshi muscular dystrophy 3, as well as autosomal dominant gnathodiaphyseal dysplasia through a predicted gain-of-function mechanism. The muscular dystrophies result from impaired membrane repair, while the bone dysplasia represents a distinct dominant phenotype.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

GeneReviews ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.95

VCEP Guidelines: Limb Girdle Muscular DystrophyReleased

ClinGen Panel

Clinical Summary— ANO5

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Gene-Disease Validity (ClinGen)

gnathodiaphyseal dysplasia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

207 unique Pathogenic / Likely Pathogenic· 757 VUS of 1543 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ANO5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

0.95LOEUF

pLI 0.000

Z-score 1.86

OE 0.73 (0.57–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.12Z-score

OE missense 0.98 (0.91–1.06)

467 obs / 474.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.57–0.95)

0≤0.351.4

Missense OE?0.98 (0.91–1.06)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 42 / 57.2Missense obs/exp: 467 / 474.2Syn Z: -1.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateANO5-related gnathodiaphyseal dysplasiaGOFAD

This gene — mechanism propensity

0.7228th %ile

GOF

0.76top 25%

LOF

0.2385th %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 · 1 literature citation

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.

Literature Evidence

GOFGain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia.1

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

References

1.PMID 29124309 ↗

ClinVar Variant Classifications

1543 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic110

Likely Pathogenic97

VUS757

Likely Benign406

Benign72

Conflicting91

110

Pathogenic

Likely Pathogenic

757

VUS

406

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	84	12	14	0	110
Likely Pathogenic	64	24	9	0	97
VUS	19	596	130	12	757
Likely Benign	1	9	241	155	406
Benign	0	2	67	3	72
Conflicting	—				91
Total	168	643	461	170	1,533

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap ANO5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →