7-150948519-C-T

Position:

chr7-150948519-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000238.4(KCNH2):c.2617G>A(p.Gly873Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 1.67

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035688758).

BP6

Variant 7-150948519-C-T is Benign according to our data. Variant chr7-150948519-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 67419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948519-C-T is described in Lovd as [Benign]. Variant chr7-150948519-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 124 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2617G>A	p.Gly873Ser	missense_variant	11/15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.2617G>A	p.Gly873Ser	missense_variant	11/15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1597G>A	p.Gly533Ser	missense_variant	7/11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3450G>A		non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000188

AC:

AN:

250272

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135470

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1461448

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00239

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000814

AC:

124

AN:

152258

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00270

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.000914

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:16487223;PMID:14661677;PMID:16043162;PMID:19841300). -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KCNH2 p.Gly533Ser variant was identified in 1 of 156 proband chromosomes (frequency: 0.0064) from a 57 year old Han Chinese woman with Brugada syndrome; the variant was also found in in 2 of 1000 control chromosomes (frequency: 0.002) from healthy Han Chinese individuals (Verker_2005_PMID:16043162). In a study of 744 apparently healthy individuals, the p.G533S variant was identified in 0.3% of African individuals but was not identified in the Caucasian, Asian or Hispanic individuals (Ackerman_2003_PMID:14661677). Another study identified the variant at a frequency of 0.002 in 265 healthy Chinese individuals (Koo_2006_PMID:16487223). The variant was identified in dbSNP (ID: rs41314354), LOVD 3.0 and ClinVar (classified as likely benign by Invitae, Color and Biesecker Lab/Clinical Genomics Section, National Institutes of Health). The variant was identified in control databases in 74 of 281626 chromosomes at a frequency of 0.0002628 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 57 of 24918 chromosomes (freq: 0.002288), East Asian in 13 of 19928 chromosomes (freq: 0.000652), Latino in 2 of 35424 chromosomes (freq: 0.000056) and European (non-Finnish) in 2 of 128482 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a difference in splicing. The p.Gly533 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Functional data suggest that the p.G533S variant may be a modifer of K+ channel function (Verker_2005_PMID:16043162). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	Reported in association with Brugada syndrome and hypertrophic cardiomyopathy (Verkerk et al., 2005; Lopes et al., 2015); Also observed in multiple control individuals and individuals who underwent genetic testing for indications unrelated to cardiomyopathy, arrhythmia or a family history of sudden cardiac death (Ackerman et al., 2003; Verkerk et al., 2005; Koo et al., 2006; Kapa et al., 2009; Ng et al., 2013; Ghouse et al., 2016; Van Driest et al., 2016); Reported in ClinVar (ClinVar Variant ID# 67419; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32145446, 30821013, 16043162, 22949429, 26746457, 27711072, 19841300, 16487223, 14661677, 23861362, 25351510, 23414114) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 31, 2019

Variant summary: KCNH2 c.2617G>A (p.Gly873Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 278760 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0023 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Verkerk et al. (2005) reported c.2617G>A in a patient affected with Brugada syndrome and carried out functional assessments to determine the effect of the variant on protein function. A a negative shift of voltage-dependent inactivation resulting in increased rectification was noted and increased transient peak currents of the ventricular action potential were described. These results do not support an association of this finding with the established pathophysiology of disease in LQT2 (decreased rapid delayed rectifier potassium current) and Brugada syndrome (KCNH2 is not widely recognized as a gene causative of Brugada syndrome). Therefore, these findings do not provide unequivocal conclusions about association of the variant with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 08, 2021

- -

KCNH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2021

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

Oct 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.31

.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.036

T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

-0.14

.;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.020

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.84

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.26

B;P

Vest4

0.21

MVP

0.89

MPC

0.17

ClinPred

0.026

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.041

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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