chr11-26332292-G-T

Position:

• chr11-26332292-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_031418.4(ANO3):​c.17G>T​(p.Gly6Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO3	NM_031418.4	c.17G>T	p.Gly6Val	missense_variant	1/27	ENST00000256737.8	NP_113606.2
ANO3	XM_047427399.1	c.17G>T	p.Gly6Val	missense_variant	1/26		XP_047283355.1
ANO3	NM_001313726.2	c.229+22573G>T		intron_variant			NP_001300655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.17G>T	p.Gly6Val	missense_variant	1/27	1	NM_031418.4	ENSP00000256737	P3
ANO3	ENST00000531646.1	c.17G>T	p.Gly6Val	missense_variant	1/5	4		ENSP00000435275
ANO3	ENST00000525139.5	c.-3+22573G>T		intron_variant		5		ENSP00000432576
ANO3	ENST00000672621.1	c.229+22573G>T		intron_variant				ENSP00000500506

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Alfa AF: 0.000102 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANO3 protein function. This variant has not been reported in the literature in individuals affected with ANO3-related conditions. This variant is present in population databases (rs762765259, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the ANO3 protein (p.Gly6Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.075	T;D
Polyphen		1.0	D;.
Vest4		0.65
MutPred		0.30		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.62
MPC		0.29
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs762765259; hg19: chr11-26353839;