7-150948446-T-G

Position:

chr7-150948446-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The ENST00000262186.10(KCNH2):c.2690A>C(p.Lys897Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,097,454 control chromosomes in the GnomAD database, including 40,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K897M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.21 ( 2640 hom., cov: 27)

Exomes 𝑓: 0.32 ( 37449 hom. )

Consequence

KCNH2
ENST00000262186.10 missense, splice_region

Scores

Splicing: ADA: 0.00001136

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 2.77

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 -16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in ENST00000262186.10

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150948445-CT-G is described in ClinVar as [Pathogenic]. Clinvar id is 200658.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014851391).

BP6

Variant 7-150948446-T-G is Benign according to our data. Variant chr7-150948446-T-G is described in ClinVar as [Benign]. Clinvar id is 67427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948446-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2690A>C	p.Lys897Thr	missense_variant, splice_region_variant	11/15	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.2690A>C	p.Lys897Thr	missense_variant, splice_region_variant	11/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1670A>C	p.Lys557Thr	missense_variant, splice_region_variant	7/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3523A>C		splice_region_variant, non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

24594

AN:

116886

Hom.:

2636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0586

Gnomad AMI

AF:

0.323

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.0729

Gnomad SAS

AF:

0.266

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.283

Gnomad OTH

AF:

0.230

GnomAD3 exomes

AF:

0.181

AC:

43182

AN:

238268

Hom.:

4578

AF XY:

0.191

AC XY:

24881

AN XY:

130116

show subpopulations

Gnomad AFR exome

AF:

0.0374

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.0477

Gnomad SAS exome

AF:

0.208

Gnomad FIN exome

AF:

0.165

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.325

AC:

318343

AN:

980560

Hom.:

37449

Cov.:

AF XY:

0.320

AC XY:

159155

AN XY:

497778

show subpopulations

Gnomad4 AFR exome

AF:

0.0631

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.295

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.233

Gnomad4 FIN exome

AF:

0.252

Gnomad4 NFE exome

AF:

0.359

Gnomad4 OTH exome

AF:

0.319

GnomAD4 genome

AF:

0.210

AC:

24588

AN:

116894

Hom.:

2640

Cov.:

AF XY:

0.208

AC XY:

11756

AN XY:

56486

show subpopulations

Gnomad4 AFR

AF:

0.0586

Gnomad4 AMR

AF:

0.211

Gnomad4 ASJ

AF:

0.230

Gnomad4 EAS

AF:

0.0727

Gnomad4 SAS

AF:

0.266

Gnomad4 FIN

AF:

0.256

Gnomad4 NFE

AF:

0.283

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.221

Hom.:

8778

Bravo

AF:

0.155

TwinsUK

AF:

0.247

AC:

917

ALSPAC

AF:

0.242

AC:

933

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.233

AC:

2000

ExAC

AF:

0.180

AC:

21831

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 16, 2015	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.Lys897Thr Yang et al (2002) observed the p.Lys897Thr variant in KCNH2 in 20% of drug-induced long QT cases and controls. 12-24% of individuals in the general population have this variant. In different studies of genetic variants associated with QT length variability in the general population (i.e. not long QT syndrome) p.Lys897Thr has been associated with both prolongation (Pfeufer et al 2005, Paavonen et al 2003, Newton-Cheh et al 2007) and shortening (Laitinen et al 2000, Bezzina et al 2003, Marjamaa et al 2009) of the QT interval. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, 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: Frequency in ESP (all): 2199/13006=16.9% -

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:10807545;PMID:11997281;PMID:12402336;PMID:12829173;PMID:14661677;PMID:14760488;PMID:15599693;PMID:16116052;PMID:16132053;PMID:16487223;PMID:17161064;PMID:17210839;PMID:18060054;PMID:18222980;PMID:18808722;PMID:19841300). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	This variant is associated with the following publications: (PMID: 20215044, 19019189, 28336205, 31557540, 31522018, 29874175, 18222980, 14499861, 20181576, 26846766, 27153395, 16472284, 10862094, 23303164, 26109178, 22949429, 18791070, 22338672, 16116052, 21164565, 24388587, 12829173, 21831960, 14975928) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Long QT syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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. -

Long QT syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -

Atrial fibrillation

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

May 08, 2019

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. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Cardiac arrhythmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;L

MutationTaster

Benign

0.13

P;P;P

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.23

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.25

B;B

Vest4

0.53

MPC

0.20

ClinPred

0.013

GERP RS

-0.036

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.084

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.024

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