rs146284716

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000238.4(KCNH2):c.431A>T(p.Asp144Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,988 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). Synonymous variant affecting the same amino acid position (i.e. D144D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.753

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 -5 ACMG points.

PM1

In a domain PAC (size 52) in uniprot entity KCNH2_HUMAN there are 23 pathogenic changes around while only 5 benign (82%) in NM_000238.4

BP4

Computational evidence support a benign effect (MetaRNN=0.20533708).

BP6

Variant 7-150959613-T-A is Benign according to our data. Variant chr7-150959613-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526910.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

BS2

High AC in GnomAd at 16 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.431A>T	p.Asp144Val	missense_variant	3/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.431A>T	p.Asp144Val	missense_variant	3/15	1	NM_000238.4	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.654A>T		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1264A>T		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000478

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251152

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

GnomAD4 genome

AF:

0.000105

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.0000654

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:

0.000478

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 144 of the KCNH2 protein (p.Asp144Val). This variant is present in population databases (rs146284716, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 526910). 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. -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.431A>T (p.D144V) alteration is located in exon 3 (coding exon 3) of the KCNH2 gene. This alteration results from a A to T substitution at nucleotide position 431, causing the aspartic acid (D) at amino acid position 144 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

KCNH2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2022

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). -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostArm

Benign

0.0073

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.030

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.39

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.46

Sift

Benign

0.17

Sift4G

Benign

0.23

Polyphen

0.94

Vest4

0.36

MVP

0.81

MPC

1.4

ClinPred

0.060

GERP RS

4.7

Varity_R

0.19

gMVP

0.63

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