rs1800172

Positions:

• chr11-2847899-G-A
• chr11-2847899-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000218.3(KCNQ1):​c.1927G>A​(p.Gly643Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,580,300 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G643D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (56 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -4.71

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034711957).
• BP6: Variant 11-2847899-G-A is Benign according to our data. Variant chr11-2847899-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2847899-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00792 (1206/152270) while in subpopulation EAS AF= 0.0427 (221/5170). AF 95% confidence interval is 0.0381. There are 17 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1927G>A	p.Gly643Ser	missense_variant	16/16	ENST00000155840.12
KCNQ1-AS1	NR_130721.1	n.778-7457C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1927G>A	p.Gly643Ser	missense_variant	16/16	1	NM_000218.3	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7457C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152152 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00616 AC: 1198 AN: 194370 Hom.: 15 AF XY: 0.00570 AC XY: 600 AN XY: 105222

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0474

Gnomad SAS exome AF: 0.00703

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00242 AC: 3451 AN: 1428030 Hom.: 56 Cov.: 31 AF XY: 0.00251 AC XY: 1772 AN XY: 707262

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.0485

Gnomad4 SAS exome AF: 0.00703

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00271

GnomAD4 genome AF: 0.00792 AC: 1206 AN: 152270 Hom.: 17 Cov.: 33 AF XY: 0.00802 AC XY: 597 AN XY: 74464

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0427

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00231 Hom.: 2

Bravo AF: 0.00875

ESP6500AA AF: 0.0195 AC: 84

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.00591 AC: 701

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly643Ser in Exon 16 of KCNQ1: This variant is not expected to have clinical sig nificance because it has been identified in 2.0% (72/3634) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs1800172). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -

not provided Benign:4 Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:9799083;PMID:10807545;PMID:11761407;PMID:14661677;PMID:15028050;PMID:15500450;PMID:16038262;PMID:16487223;PMID:17016049;PMID:18426444;PMID:19841300). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	This variant is associated with the following publications: (PMID: 30462975, 29431662, 14661677, 29021305, 29855564, 21139297, 16563243, 17222736, 15746444, 16487223, 11761407, 24388587, 28704380, 26385840, 26159999, 24284363, 24762593, 22949429, 22378279, 22677073, 24573873, 27875062) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2018	- -

Long QT syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 27, 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. -

Cardiac arrhythmia Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2013	- -

Atrial fibrillation, familial, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 27, 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. -

Jervell and Lange-Nielsen syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 27, 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. -

Short QT syndrome type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 27, 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. -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.016
DANN	Benign	0.88
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.39	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.76	N;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.58	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.080
MVP		0.67
MPC		0.37
ClinPred		0.0055	T
GERP RS		-2.9
Varity_R		0.032
gMVP		0.33

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: rs1800172; hg19: chr11-2869129; COSMIC: COSV50110156;