rs794728356

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000238.4(KCNH2):c.563C>T(p.Ala188Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000154 in 1,432,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A188T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.592

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16126326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.563C>T	p.Ala188Val	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.563C>T	p.Ala188Val	missense_variant	4/15	1	NM_000238.4	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.786C>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1396C>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

150984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1281020

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

630312

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

150984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

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:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2013

p.Ala188Val (GCG>GTG): c.563 C>T in exon 4 of the KCNH2 (aka HERG) gene (NM_000238.2). The Ala188Val variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala188Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is not well conserved across species. In silico analysis predicts Ala188Val is benign to the protein structure/function. Nevertheless, the Ala188Val variant was not observed in approximately 3,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Also, a mutation in a nearby codon (Arg176Trp) has been reported in association with LQTS, supporting the functional importance of this region of the protein. With the clinical and molecular information available at this time, we cannot definitively determine if Ala188Val is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 05, 2023

ClinVar contains an entry for this variant (Variation ID: 200293). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the KCNH2 protein (p.Ala188Val). This variant is not present in population databases (gnomAD no frequency). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The p.A188V variant (also known as c.563C>T), located in coding exon 4 of the KCNH2 gene, results from a C to T substitution at nucleotide position 563. The alanine at codon 188 is replaced by valine, an amino acid with similar properties. This alteration has been reported in an arrhythmia genetic testing cohort; however, clinical details were limited (Van Driest SL et al. JAMA, 2016 Jan;315:47-57). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

CardioboostArm

Benign

0.000023

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

Cadd

Benign

9.0

Dann

Benign

0.91

DEOGEN2

Benign

0.32

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.14

REVEL

Uncertain

0.36

Sift

Benign

0.45

Sift4G

Benign

0.51

Polyphen

0.0030

Vest4

0.14

MutPred

0.41

Loss of disorder (P = 0.0912);

MVP

0.67

MPC

1.0

ClinPred

0.049

GERP RS

2.1

Varity_R

0.013

gMVP

0.26

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