rs146532706

Positions:

• chr11-26525656-C-A
• chr11-26525656-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031418.4(ANO3):​c.714C>A​(p.Asp238Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D238D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22096983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO3	NM_031418.4	c.714C>A	p.Asp238Glu	missense_variant	7/27	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.714C>A	p.Asp238Glu	missense_variant	7/27	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000672621.1	c.897C>A	p.Asp299Glu	missense_variant	8/28			ENSP00000500506.1
ANO3	ENST00000525139.5	c.666C>A	p.Asp222Glu	missense_variant	7/27	5		ENSP00000432576.1
ANO3	ENST00000531568.1	c.276C>A	p.Asp92Glu	missense_variant	4/24	2		ENSP00000432394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.072	T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.93	.;L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.83	.;P;.
Vest4		0.48
MutPred		0.35		.;Gain of helix (P = 0.0325);.;
MVP		0.44
MPC		0.23
ClinPred		0.36	T
GERP RS		-0.050
Varity_R		0.081
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs146532706; hg19: chr11-26547203;