rs117748217

chr11-26660309-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_031418.4(ANO3):c.2811C>T(p.Asp937=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,613,220 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (111 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.861

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 11-26660309-C-T is Benign according to our data. Variant chr11-26660309-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 412868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-26660309-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.861 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00754 (1148/152220) while in subpopulation AMR AF= 0.014 (214/15260). AF 95% confidence interval is 0.0125. There are 11 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_031418.4	c.2811C>T	p.Asp937=	synonymous_variant	27/27	ENST00000256737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000256737.8	c.2811C>T	p.Asp937=	synonymous_variant	27/27	1	NM_031418.4	P3
ANO3	ENST00000672621.1	c.2994C>T	p.Asp998=	synonymous_variant	28/28
ANO3	ENST00000525139.5	c.2763C>T	p.Asp921=	synonymous_variant	27/27	5
ANO3	ENST00000531568.1	c.2373C>T	p.Asp791=	synonymous_variant	24/24	2		A1

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1147 AN: 152102 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00873 AC: 2189 AN: 250776 Hom.: 21 AF XY: 0.00913 AC XY: 1238 AN XY: 135552

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00643

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00965 AC: 14097 AN: 1461000 Hom.: 111 Cov.: 31 AF XY: 0.00966 AC XY: 7020 AN XY: 726792

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0340

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00634

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00993

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00754 AC: 1148 AN: 152220 Hom.: 11 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74416

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00907

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0101 Hom.: 6

Bravo AF: 0.00879

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0144

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ANO3: BP4, BP7, BS1, BS2 -

Dystonia 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	11
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs117748217; hg19: chr11-26681856; COSMIC: COSV56792910;