rs138776684

Positions:

chr7-150957380-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000238.4(KCNH2):c.1039C>T(p.Pro347Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,000 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:14O:1

Conservation

PhyloP100: 0.436

Variant links:

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010891318).

BS2

High AC in GnomAd4 at 97 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.1039C>T	p.Pro347Ser	missense_variant	5/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.1039C>T	p.Pro347Ser	missense_variant	5/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.1262C>T		non_coding_transcript_exon_variant	5/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1872C>T		non_coding_transcript_exon_variant	3/13

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00106

AC:

265

AN:

250142

Hom.:

AF XY:

0.00120

AC XY:

162

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.00114

AC:

1659

AN:

1461614

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

872

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00282

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000637

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.000567

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:14Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5Other: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:10973849;PMID:12402336;PMID:14661677;PMID:14760488;PMID:16432067;PMID:19841300;PMID:21410720;PMID:22378279). -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	KCNH2: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Long QT syndrome 2

Uncertain:3Benign:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	May 17, 2018	- -

Long QT syndrome

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 25, 2022	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 18, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Pro347Ser Given an MAF of 0.2% in unselected individuals and the location in the protein, we consider this variant likely benign. The proline at codon 347 is not conserved across species. The variant is in the N terminus of the channel. Variants in this region are less likely to be pathogenic than variants in the channel or C terminus (Kapa et al 2009). The variant was reported online in 156 of 55,452 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 16, 2015). Specifically, the variant was observed in 38 of 7642 South Asian individuals (MAF 0.2%)and 111 of 30,876 European indivdiuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD associated to LQTS in 9 papers, with comments suggesting Benign-VUS. It is classified in ClinVar with 1 star as Benign by Stanford and Invitae, Likely benign by Biesecker lab, and VUS by GeneDx and CSER. It has a Max MAF in ExAC of 0.24% (38 South Asian alleles) and in gnomAD of 0.25% (78 South Asian, 21 Ashkenazi, and 160 european alleles). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2018

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. -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2018

- -

KCNH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

-0.070

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.63

D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

N;.

REVEL

Uncertain

0.55

Sift

Benign

0.46

T;.

Sift4G

Benign

0.71

T;T

Polyphen

0.76

P;.

Vest4

0.22

MVP

0.98

MPC

1.3

ClinPred

0.025

GERP RS

4.8

Varity_R

0.11

gMVP

0.75

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

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