NM_031418.4:c.702C>A

Variant names:

• chr11-26525644-C-A
• rs886037882
• NM_031418.4:c.702C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031418.4(ANO3):​c.702C>A​(p.Cys234*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO3 NM_031418.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.745

Genes affected

ANO3 (HGNC:14004): (anoctamin 3) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4	c.702C>A	p.Cys234*	stop_gained	Exon 7 of 27	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.702C>A	p.Cys234*	stop_gained	Exon 7 of 27	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000672621.1	c.885C>A	p.Cys295*	stop_gained	Exon 8 of 28			ENSP00000500506.1
ANO3	ENST00000525139.5	c.654C>A	p.Cys218*	stop_gained	Exon 7 of 27	5		ENSP00000432576.1
ANO3	ENST00000531568.1	c.264C>A	p.Cys88*	stop_gained	Exon 4 of 24	2		ENSP00000432394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 24 Uncertain:1

Aug 25, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.702C>A, p.Cys234Ter nonsense variant identified in the ANO3 gene has not been reported in the literature. This variant is absent from in the gnomAD v3.1.1 database suggesting it is not a common benign variant in the populations represented in this database. This variant creates a premature translational stop signal atexon 15 of 22 and is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ANO3 cause disease. Based on the available evidence, the nonsense variant c.702C>A, p.Cys234Ter in the ANO3 gene is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.82	D
Vest4		0.84
GERP RS		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886037882; hg19: chr11-26547191;