11-26189234-C-T

Position:

• chr11-26189234-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP5_Moderate BP4 BS1_Supporting BS2

The NM_001313726.2(ANO3):​c.58C>T​(p.His20Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 984,950 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (76 hom.)
• Consequence: ANO3 NM_001313726.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.248

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.

• PP5: Variant 11-26189234-C-T is Pathogenic according to our data. Variant chr11-26189234-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3362365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1571/152236) while in subpopulation SAS AF= 0.0168 (81/4828). AF 95% confidence interval is 0.0138. There are 10 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1571 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_001313726.2	c.58C>T	p.His20Tyr	missense_variant	1/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000672621.1	c.58C>T	p.His20Tyr	missense_variant	1/28
ANO3	ENST00000531798.1	n.112C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1571 AN: 152118 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.00833

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0137 AC: 11377 AN: 832714 Hom.: 76 Cov.: 29 AF XY: 0.0138 AC XY: 5303 AN XY: 384546

Gnomad4 AFR exome AF: 0.00190

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.00725

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0103 AC: 1571 AN: 152236 Hom.: 10 Cov.: 32 AF XY: 0.0107 AC XY: 796 AN XY: 74426

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00832

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0103 Hom.: 1

Bravo AF: 0.00957

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 24 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed inframe deletion c.1521_1523del(p.Phe508del) variant in CFTR gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with cystic fibrosis (Murer C, et al., 2018; Watson MS, et al., 2004; Sosnay PR, et al., 2013). This variant has also been observed to segregate with disease in related individuals. This variant is the most common variant identified in the CFTR gene, with up to 90% of individuals with cystic fibrosis (CF) having at least one copy of the c.1521_1523delCTT variant (Cai Z, et al., 2011). Experimental studies have shown that this variant affects CFTR function (Sosnay PR, et al., 2013). The p.Phe508del variant has been reported with allele frequency of 0.7% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Phe508del causes deletion of amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.9
DANN	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs118112197; hg19: chr11-26210781;