chr7-150947428-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000238.4(KCNH2):c.3052C>G(p.Pro1018Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,556,376 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.46

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2766472).

BS2

High AC in GnomAdExome4 at 56 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.3052C>G	p.Pro1018Ala	missense_variant	Exon 13 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 link	c.3052C>G	p.Pro1018Ala	missense_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 link	c.2032C>G	p.Pro678Ala	missense_variant	Exon 9 of 11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 link	n.3885C>G		non_coding_transcript_exon_variant	Exon 11 of 13

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152124

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000256

AC:

AN:

156200

Hom.:

AF XY:

0.0000355

AC XY:

AN XY:

84544

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000402

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:

0.0000495

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000399

AC:

AN:

1404134

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

693004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000277

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:

0.0000490

Gnomad4 OTH exome

AF:

0.0000343

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74456

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000908

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 12, 2021	The KCNH2 c.3052C>G; p.Pro1018Ala variant (rs41313764) is reported in the literature in an individual affected with atrial fibrillation, though it was not demonstrated to be disease-causing (Donate Puertas 2018). This variant is found on only four chromosomes (4/156200 alleles) in the Genome Aggregation Database. The proline at codon 1018 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro1018Ala variant is uncertain at this time. References: Donate Puertas R et al. Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation. Biomed Res Int. 2018;2018:4862480. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	Reported in individuals with various cardiac disorders, including dilated cardiomyopathy, ventricular tachycardia, paroxysmal atrial fibrillation, and unspecified arrhythmia (Doate Puertas et al., 2018; Herkert et al., 2018; van Lint et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29517769, 30847666, 30276209) -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2024	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1018 of the KCNH2 protein (p.Pro1018Ala). This variant is present in population databases (rs41313764, gnomAD 0.005%). This missense change has been observed in individual(s) with atrial fibrillation, unknown arrhythmia, left ventricular noncompaction and dilated cardiomyopathy (PMID: 28798025, 29517769, 30276209, 30847666). ClinVar contains an entry for this variant (Variation ID: 200520). 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. 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	Nov 30, 2023	This missense variant replaces proline with alanine at codon 1018 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmias (PMID: 30276209, 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 28798025). This variant has been identified in 4/156200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 19, 2022

This missense variant replaces proline with alanine at codon 1018 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmias (PMID: 30276209, 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 28798025). This variant has been identified in 4/156200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.35

.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.4

.;L

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.56

Sift

Benign

0.24

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0060

B;B

Vest4

0.25

MutPred

0.27

.;Loss of glycosylation at P1018 (P = 0.02);

MVP

0.85

MPC

0.65

ClinPred

0.094

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Varity_R

0.086

gMVP

0.54

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