7-150974903-A-G

Position:

chr7-150974903-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBS2_Supporting

The NM_000238.4(KCNH2):c.115T>C(p.Cys39Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 9.18

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:

KCNH2 (HGNC:):

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

BS2

High AC in GnomAd4 at 8 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.115T>C	p.Cys39Arg	missense_variant	2/15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.115T>C	p.Cys39Arg	missense_variant	2/15	1	NM_000238.4	ENSP00000262186.5		Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.338T>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

243308

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132524

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000551

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1458840

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725708

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:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

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	Oct 20, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 39 of the KCNH2 protein (p.Cys39Arg). This variant is present in population databases (rs757491162, gnomAD 0.006%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23174487). ClinVar contains an entry for this variant (Variation ID: 456883). 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 disruptive. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 26958806, 31557540). 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	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 16, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2021

The p.C39R variant (also known as c.115T>C), located in coding exon 2 of the KCNH2 gene, results from a T to C substitution at nucleotide position 115. The cysteine at codon 39 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the N-terminal region of the protein. This variant has been reported in an individual with long QT syndrome (LQTS), who also had other LQTS-associated variants (Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82;). This variant was also reported in three individuals in an LQTS cohort; however, clinical details were limited (Kim JA et al. Heart Rhythm, 2010 Dec;7:1797-805). Limited functional studies have demonstrated membrane expression that is similar to wild-type levels (Perry MD et al. J. Physiol. (Lond.), 2016 07;594:4031-49; Ng CA et al. Heart Rhythm, 2020 03;17:492-500). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 06, 2021

- -

KCNH2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2023

The KCNH2 c.115T>C variant is predicted to result in the amino acid substitution p.Cys39Arg. This variant was reported in 3 individuals from a cohort of long-QT syndrome type-2 (LQT2) patients, although no additional clinical information was provided (Kim JA et al. 2010. PubMed ID: 20850565). This variant, along with several other variants, was reported in another individual with Long QT syndrome (Mullally et al 2013. PubMed ID: 23174487). In vitro functional studies show that this variant results in cell surface protein expression within ±10% compared to control, and in an electrophysiological functional study, showed similar gating kinetics to control (Perry MD et al. 2016. PubMed ID: 26958806; Ng CA et al 2019. PubMed ID: 31557540). This variant is reported in 0.0055% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-150671991-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.93

Sift

Benign

0.067

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.98

MutPred

0.68

Gain of MoRF binding (P = 0.0313);

MVP

0.98

MPC

2.8

ClinPred

0.73

GERP RS

4.1

Varity_R

0.96

gMVP

0.99

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