11-2445305-G-T

Position:

chr11-2445305-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000218.3(KCNQ1):c.207G>T(p.Ala69Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,439,640 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 6 hom. )

Consequence

KCNQ1
NM_000218.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.16

Variant links:

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 links:

KCNQ1 (HGNC:):

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 11-2445305-G-T is Benign according to our data. Variant chr11-2445305-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 138010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2445305-G-T is described in Lovd as [Benign]. Variant chr11-2445305-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.16 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.207G>T	p.Ala69Ala	synonymous_variant	1/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 linkuse as main transcript	c.207G>T	p.Ala69Ala	synonymous_variant	1/15		NP_001393765.1
KCNQ1	NM_001406838.1 linkuse as main transcript	c.207G>T	p.Ala69Ala	synonymous_variant	1/11		NP_001393767.1
KCNQ1	NM_001406837.1 linkuse as main transcript	c.-156G>T		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.207G>T	p.Ala69Ala	synonymous_variant	1/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.207G>T	p.Ala69Ala	synonymous_variant	1/11			ENSP00000495806.2	A0A2R8YEQ9
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.24-78G>T		intron_variant		5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000345015.4 linkuse as main transcript	n.-17G>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000404

AC:

AN:

150910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00139

Gnomad ASJ

AF:

0.000579

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000384

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.000543

AC:

AN:

97640

Hom.:

AF XY:

0.000602

AC XY:

AN XY:

56448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000188

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000520

Gnomad OTH exome

AF:

0.00122

GnomAD4 exome

AF:

0.000380

AC:

490

AN:

1288628

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

249

AN XY:

635356

show subpopulations

Gnomad4 AFR exome

AF:

0.000517

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.00117

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000280

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000288

Gnomad4 OTH exome

AF:

0.000873

GnomAD4 genome

AF:

0.000397

AC:

AN:

151012

Hom.:

Cov.:

AF XY:

0.000379

AC XY:

AN XY:

73808

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.000579

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000384

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000506

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2016	p.Ala69Ala variant in exon 1 of KCNQ1: This variant is not expected to have cli nical significance because it does not alter an amino acid residue, it is not lo cated within the splice consensus sequence, and it has been identified in 0.3% ( 10/3698) of European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 22, 2016	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	KCNQ1: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 19, 2018

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Atrial fibrillation, familial, 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 19, 2018

Jervell and Lange-Nielsen syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 19, 2018

Short QT syndrome type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 19, 2018

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2016

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.6

DANN

Benign

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over