rs150817714

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000238.4(KCNH2):c.568G>A(p.Ala190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,428,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A190S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: 1.90

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1471112).

BP6

Variant 7-150958407-C-T is Benign according to our data. Variant chr7-150958407-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67512.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1, not_provided=1}. Variant chr7-150958407-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd at 108 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	4/15	1	NM_000238.4	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.791G>A		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1401G>A		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

108

AN:

150782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

0.00

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000144

AC:

AN:

48596

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

28538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000741

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:

0.00

Gnomad OTH exome

AF:

0.000678

GnomAD4 exome

AF:

0.0000619

AC:

AN:

1277188

Hom.:

Cov.:

AF XY:

0.0000462

AC XY:

AN XY:

628120

show subpopulations

Gnomad4 AFR exome

AF:

0.00253

Gnomad4 AMR exome

AF:

0.000594

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:

0.00

Gnomad4 OTH exome

AF:

0.0000949

GnomAD4 genome

AF:

0.000716

AC:

108

AN:

150892

Hom.:

Cov.:

AF XY:

0.000664

AC XY:

AN XY:

73766

show subpopulations

Gnomad4 AFR

AF:

0.00253

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000865

ExAC

AF:

0.0000458

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2018	Variant summary: KCNH2 c.568G>A (p.Ala190Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.00085 in 31934 control chromosomes (gnomAD and publication controls). The observed variant frequency within African control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.568G>A, has been reported in the literature in individuals affected with Arrhythmia. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 03, 2020	- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 190 of the KCNH2 protein (p.Ala190Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 29752375). ClinVar contains an entry for this variant (Variation ID: 67512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2020

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. -

KCNH2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

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). -

not provided

Other: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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

CardioboostArm

Benign

0.000026

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.33

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.15

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.080

REVEL

Uncertain

0.41

Sift

Benign

0.53

Sift4G

Benign

0.45

Polyphen

0.41

Vest4

0.19

MVP

0.86

MPC

0.99

ClinPred

0.044

GERP RS

2.1

Varity_R

0.028

gMVP

0.28

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