rs139544114

Positions:

Variant summary

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

The NM_000238.4(KCNH2):c.442C>T(p.Arg148Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,614,080 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts 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: 0.00082 ( 7 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:13O:1

Conservation

PhyloP100: 2.88

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=0.012147158).

BS2

High AC in GnomAd4 at 98 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.442C>T	p.Arg148Trp	missense_variant	3/15	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.442C>T	p.Arg148Trp	missense_variant	3/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.665C>T		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1275C>T		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00122

AC:

307

AN:

250940

Hom.:

AF XY:

0.00110

AC XY:

149

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.0162

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000627

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000817

AC:

1195

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000814

AC XY:

592

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.0151

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000511

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.000644

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00105

AC:

128

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KCNH2: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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:19322600;PMID:19841300;PMID:21410720). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	The R148W variant has been observed in 0.1% global alleles, including 1.6% of alleles from individuals of Ashkenazi Jewish ancestry and three individuals reported to be homozygous, in large population cohorts (Lek et al., 2016).; This variant is associated with the following publications: (PMID: 17088455, 19322600, 19841300, 20400443, 21410720, 22949429, 24055113, 23465283, 24334129, 25637381, 26159999, 27153395, 27875062, 27650965, 28988457, 31043699, 32048431) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Long QT syndrome

Uncertain:2Benign:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PP2, PP3, BS1 -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 18, 2013	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.Arg148Trp Given the data reviewed below we also consider it a variant of uncertain significance. Millat et al (2009) observed the variant in a 4mo male SIDS case. Kapa et al (2009) report the variant as a polymorphism. They do not provide the frequency of the variant in controls but note that they considered something a polymorphism if it was seen more than once in the 1369 controls they studied. This same group reported the variant in a case of autopsy-negative sudden cardiac death but noted it was a "less common polymorphism" without functional data supporting pathogenicity. Novotny et al (2011) sequenced several long QT genes in individuals with coronary artery disease and ventricular fibrillation and observed this variant in one individual. Crotti et al (2012) reported the variant in one individual with long QT syndrome. No ancestry or segregation data were provided. The variant is in the N-terminal region of the protein. In total the variant has been seen in 25 of 7164 individuals in publicly available general population samples. The variant is listed in dbSNP (rs139544114), pointing to the NHLBI ESP data and also noting that ~9/661 individuals in the ClinSeq population from NIH (a general population cohort) were heterozygotes. The variant was reported online in 16 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 18th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	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: Multiple reports as VUS/polymorphism, ExAC: 0.1% (99/66588) European chromosomes -

Long QT syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Conduction disorder of the heart

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 27, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2017

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

AlphaMissense

Benign

0.091

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.012

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.84

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.044

Polyphen

1.0

Vest4

0.33

MVP

0.95

MPC

1.0

ClinPred

0.044

GERP RS

3.8

Varity_R

0.23

gMVP

0.61

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