rs11024034

Positions:

• chr11-2768933-T-C

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.1590+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,605,040 control chromosomes in the GnomAD database, including 9,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (613 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8467 hom.)
• Consequence: KCNQ1 ENST00000155840.12 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: -0.0630

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=-0.84).
• BP6: Variant 11-2768933-T-C is Benign according to our data. Variant chr11-2768933-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 36436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2768933-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1590+14T>C		intron_variant		ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1590+14T>C		intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.1209+14T>C		intron_variant		1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.1233+14T>C		intron_variant		5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.1050+14T>C		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11836 AN: 152076 Hom.: 614 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0659

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0874

GnomAD3 exomes AF: 0.0861 AC: 21597 AN: 250926 Hom.: 1111 AF XY: 0.0901 AC XY: 12228 AN XY: 135712

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0745

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.103 AC: 150175 AN: 1452846 Hom.: 8467 Cov.: 30 AF XY: 0.103 AC XY: 74763 AN XY: 723404

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0486

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0759

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.0949

GnomAD4 genome AF: 0.0778 AC: 11834 AN: 152194 Hom.: 613 Cov.: 32 AF XY: 0.0770 AC XY: 5732 AN XY: 74408

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0646

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0668

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0855

Alfa AF: 0.0904 Hom.: 204

Bravo AF: 0.0730

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	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	1590+14T>C in Intron 12 of KCNQ1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 11.5% (806/7020) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs11024034). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2012	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. -

not provided Uncertain:1 Benign:2

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: 12.169% in gnomAD_ExomesFounderPop) 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.A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	- -

Long QT syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atrial fibrillation, familial, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jervell and Lange-Nielsen syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Short QT syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.78
DANN	Benign	0.54

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: rs11024034; hg19: chr11-2790163;