ANO10

protein-coding

anoctamin 10, the group of Anoctamins

Gene summary

The transmembrane protein encoded by this gene belongs to the anoctamin family of calcium-activated chloride channels, also known as the transmembrane 16 family. The encoded protein contains eight transmembrane domains with cytosolic N- and C-termini. Defects in this gene may cause autosomal recessive spinocerebellar ataxia-10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

Previous symbols:

TMEM16K

MANE transcript

NM_018075.5

Inheritance

ClinVar variants

P:113U:148B:162

Top phenotype

Spinocerebellar ataxia, autosomal recessive 10

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr3:43,354,859-43,691,594

External References & Databases

Ensembl (ENSG00000160746)

Transcript & Mutation Effects

hg38 • Region Span ~336.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spinocerebellar ataxia 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013392

Submitter: Ambry Genetics

autosomal recessive spinocerebellar ataxia 10DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013392

Submitter: ClinGen

*ANO10* was first reported in relation to autosomal recessive cerebellar ataxia in 2010 (Vermeer et al., PMID: 21092923). The *ANO10* gene is a member of the anoctamin family and encodes a transmembrane protein that has various functions including phospholipid scrambling, chloride channel activity, and calcium signaling (PMID: 35648332). Autosomal recessive cerebellar ataxia due to variants in *ANO10* is characterized by gait and limb ataxia, dysarthria, nystagmus, and cerebellar atrophy on brain imaging (PMID: 21092923). Other features may be present as well and age of onset is variable (PMID: 36698452). Six variants (2 nonsense, 2 frameshift, 1 missense, 1 canonical splice-site) that have been reported in 5 probands in 3 publications (PMIDs: 21092923, 23551081, 25133958) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is unknown. This gene-disease relationship is also supported by experimental evidence including alteration of calcium signaling in mouse intestinal epithelial cells (PMID: 27838374), alteration of endosomal retrograde transport in mouse embryonic fibroblasts (PMID: 32620747), and a knockout mouse model displaying impairment of neuromuscular function (PMID: 32620747). In summary, there is definitive evidence supporting the relationship between *ANO10* and autosomal recessive cerebellar ataxia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date December 11, 2024 (SOP Version 10).

autosomal recessive spinocerebellar ataxia 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013392

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 10SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013392

Submitter: Orphanet

autosomal recessive spinocerebellar ataxia 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013392

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 10AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21092923; 22008874

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANO10 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 385

Autosomal recessive spinocerebellar ataxia 10Total: 135

Inborn genetic diseasesTotal: 82

not specifiedTotal: 44

ANO10-related disorderTotal: 18

Abnormal central motor functionTotal: 1

AutismTotal: 1

Autosomal recessive cerebellar ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018075.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	142 clinvar	2 clinvar	146
missense	1 clinvar	4 clinvar	140 clinvar	18 clinvar		163
nonsense	27 clinvar	8 clinvar	1 clinvar			36
start loss		3 clinvar				3
frameshift	41 clinvar	10 clinvar	1 clinvar			52
splice donor/acceptor (+/-2bp)	2 clinvar	17 clinvar	4 clinvar			23
Total	71	42	148	160	2	423

Highest pathogenic variant AF is 0.0006744984

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 131 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018075.5	RefSeq	NP_060545.3	12	MANE Select
ENST00000292246.8	Ensembl	ENSP00000292246.3	12	MANE Select
NM_001204831.3	RefSeq	NP_001191760.1	11	Standard
NM_001204832.3	RefSeq	NP_001191761.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

cation transport
chloride transport
ion transmembrane transport

Molecular Function

calcium activated cation channel activity
intracellular calcium activated chloride channel activity

Cellular Component

plasma membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292246
Coding exons: 12
Length: 336736
Individuals with no LoFs: 125663
Homozygous LoFs: 0
Heterozygous LoFs: 85
Defined: 125748
p: 0.000338

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.317	327	344	0.952	0.0000176	4320
Missense (PolyPhen)		98	105.81	0.92622		1340
Synonymous	-0.953	145	131	1.11	0.00000691	1234
Loss of Function	0.986	25	30.9	0.809	0.00000137	419

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00044	0.00044	rare
South Asian	0.00040	0.00039	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Does not exhibit calcium-activated chloride channel (CaCC) activity. Can inhibit the activity of ANO1. {ECO:0000269|PubMed:20056604, ECO:0000269|PubMed:22946059}.;

Recessive Scores

pRec: 0.0956

Intolerance Scores

LoFtool: 0.872
RVIS EVS: 0.96
RVIS percentile EVS: 90.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.171

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium