7-150948477-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM5PP2BS2

The NM_000238.4(KCNH2):c.2659C>G(p.Arg887Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,610,452 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R887H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.98

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
short QT syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150948476-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67423.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2659C>G	p.Arg887Gly	missense_variant	Exon 11 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.2659C>G	p.Arg887Gly	missense_variant	Exon 11 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

150822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000979

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

249022

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1459630

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111622

Other (OTH)

AF:

0.0000166

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000265

AC:

AN:

150822

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73572

show subpopulations

African (AFR)

AF:

0.0000979

AC:

AN:

40876

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5090

South Asian (SAS)

AF:

0.00

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67864

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000154

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 887 of the KCNH2 protein (p.Arg887Gly). This variant is present in population databases (rs140279503, gnomAD no frequency). 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: 924438). 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. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glycine at codon 887 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/249022 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. -

Cardiovascular phenotype

Uncertain:1

May 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R887G variant (also known as c.2659C>G), located in coding exon 11 of the KCNH2 gene, results from a C to G substitution at nucleotide position 2659. The arginine at codon 887 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Uncertain:1

Oct 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiac arrhythmia

Uncertain:1

Mar 26, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

CardioboostArm

Benign

0.020

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

.;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

.;L

PhyloP100

4.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.019

D;D

Sift4G

Benign

0.086

T;T

Polyphen

0.97

D;P

Vest4

0.35

MutPred

0.52

.;Gain of sheet (P = 0.0036);

MVP

0.99

MPC

0.69

ClinPred

0.94

GERP RS

4.1

Varity_R

0.43

gMVP

0.90

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over