ANO6

protein-coding

anoctamin 6, the group of Anoctamins

Gene summary

This gene encodes a multi-pass transmembrane protein that belongs to the anoctamin family. This protein is an essential component for the calcium-dependent exposure of phosphatidylserine on the cell surface. The scrambling of phospholipid occurs in various biological systems, such as when blood platelets are activated, they expose phosphatidylserine to trigger the clotting system. Mutations in this gene are associated with Scott syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

Previous symbols:

TMEM16F

MANE transcript

NM_001025356.3

Inheritance

ClinVar variants

P:41U:151B:118

Top phenotype

Scott syndrome

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr12:45,215,987-45,482,280

External References & Databases

Ensembl (ENSG00000177119)

Transcript & Mutation Effects

hg38 • Region Span ~266.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Scott syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009885

Submitter: Orphanet

Scott syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009885

Submitter: PanelApp Australia

Scott syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009885

Submitter: ClinGen

*ANO6* was first reported in relation to autosomal recessive Scott syndrome in 2010 (Suzuki J, et al., PMID: 21107324). At least 6 unique variants (nonsense, splicing, frameshift, and large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 5 probands in 5 publications (PMIDs: 21107324, 21511967, 27879994, 37455884, 38492852). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of *ANO6* as a transmembrane protein essential for the calcium-dependent exposure of phosphatidylserine (PMID: 21107324), defects in which are responsible for a reduced catalytic platelet surface, which leads to reduced thrombin generation and impaired clot formation in patient cells (PMID: 27879994). Both dog and mouse models recapitulate the defect in phosphatidylserine exposure and bleeding abnormalities (PMIDs: 11895776, 23021219). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was previously evaluated by the HT GCEP on 05/27/2020 and 06/22/2022. It was reevaluated on 05/28/2025 and two new cases were identified (PMIDs: 37455884, 38492852) however the classification did not change. Of note, an additional patient has been identified but is not yet reported in the literature or ClinVar. The patient has reduced/absent thrombin generation and is compound heterozygous for p.R67X/p.E669Dfs*41.

Scott syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009885

Submitter: Labcorp Genetics (formerly Invitae)

Scott syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009885

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Scott syndromeAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Though manifestations tend to be milder than in other bleeding disorders, precautions related to certain circumstances, such as in surgery or during pregnancy and delivery, may be beneficial

Refs: 572637; 7989579; 21107324; 37455884

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANO6 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 249

Inborn genetic diseasesTotal: 126

not specifiedTotal: 53

ANO6-related disorderTotal: 26

SCOTT SYNDROMETotal: 15

Hydrocephalus, nonsyndromic, autosomal recessive 2Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001025356.3. 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	89 clinvar	3 clinvar	94
missense			148 clinvar	24 clinvar	2 clinvar	174
nonsense	15 clinvar	4 clinvar				19
start loss						0
frameshift	5 clinvar	6 clinvar				11
splice donor/acceptor (+/-2bp)	3 clinvar	8 clinvar	1 clinvar			12
Total	23	18	151	113	5	310

Highest pathogenic variant AF is 0.00019041004

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001025356.3	RefSeq	NP_001020527.2	20	MANE Select
ENST00000320560.13	Ensembl	ENSP00000320087.8	20	MANE Select
NM_001142678.2	RefSeq	NP_001136150.1	20	Standard
NM_001142679.2	RefSeq	NP_001136151.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ano6	Danio rerio	Structure: dorsal longitudinal anastomotic vessel Quality: aplastic abnormal

Gene / Model

Organism

Observed Phenotype

ano6

Danio rerio

Structure: dorsal longitudinal anastomotic vessel

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neutrophil degranulation
Stimuli-sensing channels
Ion channel transport
Innate Immune System
Immune System

Biological Process

dendritic cell chemotaxis
activation of blood coagulation via clotting cascade
cation transport
chloride transport
blood coagulation

Molecular Function

calcium activated cation channel activity
intracellular calcium activated chloride channel activity
voltage-gated ion channel activity
voltage-gated chloride channel activity
protein binding

Cellular Component

cytosol
plasma membrane
cell surface
membrane
chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000423947
Coding exons: 21
Length: 224418
Individuals with no LoFs: 125592
Homozygous LoFs: 1
Heterozygous LoFs: 155
Defined: 125748
p: 0.000620

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.902	452	509	0.888	0.0000281	6165
Missense (PolyPhen)		169	223.21	0.75714		2712
Synonymous	0.0826	179	180	0.992	0.0000101	1708
Loss of Function	0.674	51	56.5	0.903	0.00000330	622

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00049	0.00049	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00072	0.00072	rare
South Asian	0.0010	0.00098	notable
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts. Phospholipid scrambling results in surface exposure of phosphatidylserine which in platelets is essential to trigger the clotting system whereas in osteoblasts is essential for the deposition of hydroxyapatite during bone mineralization. Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide (By similarity). Can generate outwardly rectifying chloride channel currents in airway epithelial cells and Jurkat T lymphocytes. {ECO:0000250|UniProtKB:Q6P9J9, ECO:0000269|PubMed:20056604, ECO:0000269|PubMed:21107324, ECO:0000269|PubMed:21908539, ECO:0000269|PubMed:22006324, ECO:0000269|PubMed:22946059}.;

Intolerance Scores

LoFtool: 0.996
RVIS EVS: -0.08
RVIS percentile EVS: 47.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.137

Gene Damage Prediction

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