rs151031345

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000238.4(KCNH2):c.3203A>G(p.Gln1068Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,610,756 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 2.55

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34349537).

BP6

Variant 7-150947004-T-C is Benign according to our data. Variant chr7-150947004-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67480.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, not_provided=1}. Variant chr7-150947004-T-C is described in Lovd as [Benign].

BS2

High AC in GnomAd at 12 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.3203A>G	p.Gln1068Arg	missense_variant	14/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.3203A>G	p.Gln1068Arg	missense_variant	14/15	1	NM_000238.4	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.2183A>G	p.Gln728Arg	missense_variant	10/11	1			Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.4036A>G		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249548

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134922

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1458762

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725194

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other: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:14661677;PMID:19841300). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	Reported in a family with LQTS who also harbored a KCNH2 frameshift variant in trans; the p.(Q1068R) variant did not segregate with disease, whereas the frameshift variant demonstrated complete segregation with disease (Caballero et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrate an alteration in channel gating (Anson et al., 2004); however, it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 29752375, 22949429, 23303164, 14661677, 22581653, 14975928, 19841300, 30403391, 15913580, 35243873, 28049825) -

Long QT syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -
Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 06, 2019

This missense variant is located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown that this variant may accelerate channel inactivated and recovery from inactivation (PMID: 14975928). However, clinical significance of this finding is not clear. This variant has been reported in individuals apparently unaffected with cardiovascular disorders (PMID: 14661677, 19841300). In one family affected with long QT syndrome, the disease did not segregate with this variant but segregated with a truncation variant in the KCHN2 gene (PMID: 28049825). This variant has also been identified in 11/244472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant causes disease, available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostArm

Benign

0.0072

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Uncertain

0.040

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.34

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.096

T;D

Polyphen

0.78

P;P

Vest4

0.53

MVP

0.85

MPC

0.57

ClinPred

0.13

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.52

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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