rs36210421

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000238.4(KCNH2):c.3140G>T(p.Arg1047Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,542,350 control chromosomes in the GnomAD database, including 511 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 0.018 ( 61 hom., cov: 33)

Exomes 𝑓: 0.021 ( 450 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.147

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038214326).

BP6

Variant 7-150947340-C-A is Benign according to our data. Variant chr7-150947340-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36429.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Benign=12, Uncertain_significance=1}. Variant chr7-150947340-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0183 (2780/152138) while in subpopulation NFE AF= 0.0259 (1758/67958). AF 95% confidence interval is 0.0249. There are 61 homozygotes in gnomad4. There are 1492 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2780 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.3140G>T	p.Arg1047Leu	missense_variant	13/15	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.3140G>T	p.Arg1047Leu	missense_variant	13/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.2120G>T	p.Arg707Leu	missense_variant	9/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3973G>T		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2781

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0695

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.0161

AC:

2282

AN:

141590

Hom.:

AF XY:

0.0154

AC XY:

1180

AN XY:

76746

show subpopulations

Gnomad AFR exome

AF:

0.00379

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.00429

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00312

Gnomad FIN exome

AF:

0.0732

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.0214

AC:

29701

AN:

1390212

Hom.:

450

Cov.:

AF XY:

0.0207

AC XY:

14205

AN XY:

685964

show subpopulations

Gnomad4 AFR exome

AF:

0.00304

Gnomad4 AMR exome

AF:

0.00432

Gnomad4 ASJ exome

AF:

0.00382

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00364

Gnomad4 FIN exome

AF:

0.0704

Gnomad4 NFE exome

AF:

0.0234

Gnomad4 OTH exome

AF:

0.0148

GnomAD4 genome

AF:

0.0183

AC:

2780

AN:

152138

Hom.:

Cov.:

AF XY:

0.0201

AC XY:

1492

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0695

Gnomad4 NFE

AF:

0.0259

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.0173

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.00419

AC:

ESP6500EA

AF:

0.0178

AC:

139

ExAC

AF:

0.00738

AC:

670

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
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:11468227;PMID:14661677;PMID:15522280;PMID:16487223;PMID:17161064;PMID:17210839;PMID:17275752;PMID:19841300). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	This variant is associated with the following publications: (PMID: 14975928, 17275752, 22949429, 20167303, 24596401, 23303164, 27153395, 15522280, 28472724, 26412604, 31043699) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -

Long QT syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Long QT syndrome 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2019	Variant summary: KCNH2 c.3140G>T (p.Arg1047Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.027 in 171128 control chromosomes in the gnomAD database, including 44 homozygotes. The observed variant frequency is approximately 270- fold the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3140G>T has been reported in the literature in individuals affected with various cardiovascular phenotypes without strong evidence for causality (e.g. LQTS: Mazzadi_2003; SQTS: Hu_2017; Brugada Syndrome: Kauferstein_2017; drug-induced Torsades de Pointes : Sun_2014, VanDriest_2016; sudden infant death syndrome: Anson_2004, Arnestad_2007, Glengarry_2014, Smith_2018), in many cases being found in both patients and controls. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrence with another pathogenic variant has been reported (KCNH2 c.215C>A, p.Pro72Gln; internal sample), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating the impact of the variant on hERG channel activity. Several reports indicate that the biochemical activity of hERG channels in cells expressing the variant are similar to wild-type (Anson_2004, Mannikko_2010), while others others indicate that the levels of channel activation or repolarization may be altered to varying degrees in cells expressing the variant (Sun_2004, Chevalier_2007, Jou_2013). Seven ClinVar submitters (evaluation after 2014) have cited the variant four times as benign, two times as likely benign, and one time as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Sudden unexplained death

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 27, 2015

The KCNH2 Arg1047Leu variant has previously been reported as a polymorphism and suggested to be associated with increased risk to Torsades de Pointes (Mank-Seymour AR et al., 2006; Sun Z et al., 2004; Kapa S et al., 2009). It is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) with an allele frequency of 0.008 (105/11944 alleles); and the frequency in the European (non-Finnish) sub-population is 0.02 (73/3656 alleles). We identified this variant in a 16 yo boy who had a sudden cardiac arrest with no pre-morbid diagnosis and Greek ethnicity. Post-mortem examination was unremarkable and there is no family history of any cardiac disease. Based on the frequency of the KCNH2 Arg1047Leu variant in 2% of the European (non-Finnish) population, we do not expect this variant to cause disease in isolation. We therefore classify this variant as "likely benign". -

Torsades de pointes

Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 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. -

Cardiac arrhythmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

KCNH2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as 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

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;D

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.90

.;L

MutationTaster

Benign

0.57

N;N;N

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

D;N

REVEL

Uncertain

0.60

Sift

Benign

0.054

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.065

B;B

Vest4

0.53

MPC

0.45

ClinPred

0.030

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.50

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