11-2847958-C-T

Position:

• chr11-2847958-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000218.3(KCNQ1):​c.1986C>T​(p.Tyr662=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,564,370 control chromosomes in the GnomAD database, including 43,837 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2983 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40854 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:20
• Conservation: PhyloP100: -2.57

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]

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-2847958-C-T is Benign according to our data. Variant chr11-2847958-C-T is described in ClinVar as [Benign]. Clinvar id is 42489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2847958-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1986C>T	p.Tyr662=	synonymous_variant	16/16	ENST00000155840.12	NP_000209.2
KCNQ1-AS1	NR_130721.1	n.778-7516G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1986C>T	p.Tyr662=	synonymous_variant	16/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7516G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25916 AN: 152034 Hom.: 2984 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.172 AC: 30776 AN: 178672 Hom.: 3380 AF XY: 0.174 AC XY: 16631 AN XY: 95804

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.0934

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.000505

Gnomad SAS exome AF: 0.0937

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.229 AC: 323694 AN: 1412218 Hom.: 40854 Cov.: 34 AF XY: 0.227 AC XY: 157968 AN XY: 697170

Gnomad4 AFR exome AF: 0.0410

Gnomad4 AMR exome AF: 0.0994

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.000456

Gnomad4 SAS exome AF: 0.0965

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.170 AC: 25909 AN: 152152 Hom.: 2983 Cov.: 33 AF XY: 0.168 AC XY: 12493 AN XY: 74378

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0852

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.157

Alfa AF: 0.185 Hom.: 827

Bravo AF: 0.154

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Tyr662Tyr in Exon 16 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 23.6% (1636/6932) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11601907). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 46.46% in ExAC) based on the frequency threshold of 0.868% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.11 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Long QT syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

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. -

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

Feb 19, 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	-0.50
CADD	Benign	1.5
DANN	Benign	0.89

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: rs11601907; hg19: chr11-2869188; COSMIC: COSV50126746;