11-26634298-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031418.4(ANO3):c.1968C>T(p.Ile656=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,611,710 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I656I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (86 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.422

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-26634298-C-T is Benign according to our data. Variant chr11-26634298-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-26634298-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.422 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00575 (875/152186) while in subpopulation NFE AF= 0.00768 (522/68004). AF 95% confidence interval is 0.00713. There are 4 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 875 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_031418.4	c.1968C>T	p.Ile656=	synonymous_variant	19/27	ENST00000256737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000256737.8	c.1968C>T	p.Ile656=	synonymous_variant	19/27	1	NM_031418.4	P3
ANO3	ENST00000672621.1	c.2151C>T	p.Ile717=	synonymous_variant	20/28
ANO3	ENST00000525139.5	c.1920C>T	p.Ile640=	synonymous_variant	19/27	5
ANO3	ENST00000531568.1	c.1530C>T	p.Ile510=	synonymous_variant	16/24	2		A1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152068 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00768

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00632 AC: 1585 AN: 250898 Hom.: 9 AF XY: 0.00644 AC XY: 873 AN XY: 135620

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.00783

Gnomad OTH exome AF: 0.00736

GnomAD4 exome AF: 0.00810 AC: 11822 AN: 1459524 Hom.: 86 Cov.: 29 AF XY: 0.00780 AC XY: 5664 AN XY: 726228

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.0223

Gnomad4 NFE exome AF: 0.00890

Gnomad4 OTH exome AF: 0.00849

GnomAD4 genome AF: 0.00575 AC: 875 AN: 152186 Hom.: 4 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74408

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.00768

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00542 Hom.: 1

Bravo AF: 0.00434

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia 24 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

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

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.63
Dann	Benign	0.69

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: rs149050831; hg19: chr11-26655845; COSMIC: COSV56792796;