Variant rs587777907 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000238.4(KCNH2):c.656A>T(p.Asp219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,335,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 0.936

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 11 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.656A>T	p.Asp219Val	missense_variant	4/15	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.656A>T	p.Asp219Val	missense_variant	4/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.879A>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1489A>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

99608

Hom.:

AF XY:

0.0000177

AC XY:

AN XY:

56470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1335844

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

659906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000338

Gnomad4 SAS exome

AF:

0.000135

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000196

AC:

Asia WGS

AF:

0.000889

AC:

AN:

3390

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 13, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 219 of the KCNH2 protein (p.Asp219Val). 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 long QT syndrome (PMID: 25914329). ClinVar contains an entry for this variant (Variation ID: 157662). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25914329). 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. -
Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PM2, PP2 -

Long QT syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

research

McDonald Lab; Albert Einstein College of Medicine

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

T;D

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;.

REVEL

Uncertain

0.60

Sift

Benign

0.092

T;.

Sift4G

Benign

0.54

T;T

Polyphen

0.65

P;.

Vest4

0.47

MutPred

0.37

Gain of glycosylation at T216 (P = 0.0856);.;

MVP

0.88

MPC

1.4

ClinPred

0.31

GERP RS

3.4

Varity_R

0.32

gMVP

0.55

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