rs1057128

Positions:

• chr11-2776007-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000155840.12(KCNQ1):​c.1638G>A​(p.Ser546=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,572,900 control chromosomes in the GnomAD database, including 33,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S546S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2692 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30787 hom.)
• Consequence: KCNQ1 ENST00000155840.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -2.43

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-2776007-G-A is Benign according to our data. Variant chr11-2776007-G-A is described in ClinVar as [Benign]. Clinvar id is 42488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2776007-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1638G>A	p.Ser546=	synonymous_variant	13/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1638G>A	p.Ser546=	synonymous_variant	13/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.1257G>A	p.Ser419=	synonymous_variant	13/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.1281G>A	p.Ser427=	synonymous_variant	13/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.1098G>A	p.Ser366=	synonymous_variant	8/11			ENSP00000495806

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25516 AN: 152110 Hom.: 2690 Cov.: 33

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.208 AC: 39074 AN: 187994 Hom.: 4752 AF XY: 0.203 AC XY: 20297 AN XY: 99760

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.183

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.203 AC: 287746 AN: 1420672 Hom.: 30787 Cov.: 35 AF XY: 0.202 AC XY: 141579 AN XY: 702430

Gnomad4 AFR exome AF: 0.0363

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.168 AC: 25520 AN: 152228 Hom.: 2692 Cov.: 33 AF XY: 0.169 AC XY: 12606 AN XY: 74428

Gnomad4 AFR AF: 0.0460

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.185

Alfa AF: 0.194 Hom.: 5543

Bravo AF: 0.174

Asia WGS AF: 0.220 AC: 763 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser546Ser in Exon 13 of KCNQ1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 19.7% (1379/6990) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1057128). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Long QT syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Long QT syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Atrial fibrillation, familial, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jervell and Lange-Nielsen syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Short QT syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.5
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057128; hg19: chr11-2797237; COSMIC: COSV50111629; COSMIC: COSV50111629;