chr7-150951110-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000238.4(KCNH2):c.1956T>C(p.Tyr652Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,608,930 control chromosomes in the GnomAD database, including 331,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38734 hom., cov: 34)

Exomes 𝑓: 0.63 ( 292885 hom. )

Consequence

KCNH2
NM_000238.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.277

Publications

40 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 7-150951110-A-G is Benign according to our data. Variant chr7-150951110-A-G is described in ClinVar as Benign. ClinVar VariationId is 200230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.277 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.1956T>C	p.Tyr652Tyr	synonymous_variant	Exon 8 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.1956T>C	p.Tyr652Tyr	synonymous_variant	Exon 8 of 15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.701

AC:

106660

AN:

152070

Hom.:

38677

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.620

Gnomad AMR

AF:

0.654

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.898

Gnomad SAS

AF:

0.669

Gnomad FIN

AF:

0.637

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.674

GnomAD2 exomes

AF:

0.663

AC:

164327

AN:

247964

AF XY:

0.658

show subpopulations

Gnomad AFR exome

AF:

0.898

Gnomad AMR exome

AF:

0.649

Gnomad ASJ exome

AF:

0.608

Gnomad EAS exome

AF:

0.907

Gnomad FIN exome

AF:

0.633

Gnomad NFE exome

AF:

0.603

Gnomad OTH exome

AF:

0.646

GnomAD4 exome

AF:

0.630

AC:

917867

AN:

1456742

Hom.:

292885

Cov.:

AF XY:

0.631

AC XY:

456738

AN XY:

724184

show subpopulations

African (AFR)

AF:

0.901

AC:

30118

AN:

33436

American (AMR)

AF:

0.648

AC:

28940

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.608

AC:

15827

AN:

26036

East Asian (EAS)

AF:

0.910

AC:

36066

AN:

39626

South Asian (SAS)

AF:

0.671

AC:

57752

AN:

86114

European-Finnish (FIN)

AF:

0.627

AC:

32132

AN:

51278

Middle Eastern (MID)

AF:

0.644

AC:

3708

AN:

5758

European-Non Finnish (NFE)

AF:

0.608

AC:

674213

AN:

1109566

Other (OTH)

AF:

0.649

AC:

39111

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18187

36374

54562

72749

90936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18446

36892

55338

73784

92230

<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:

0.702

AC:

106780

AN:

152188

Hom.:

38734

Cov.:

AF XY:

0.704

AC XY:

52384

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.886

AC:

36799

AN:

41534

American (AMR)

AF:

0.654

AC:

10004

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2143

AN:

3470

East Asian (EAS)

AF:

0.898

AC:

4638

AN:

5166

South Asian (SAS)

AF:

0.669

AC:

3226

AN:

4822

European-Finnish (FIN)

AF:

0.637

AC:

6740

AN:

10588

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41046

AN:

67986

Other (OTH)

AF:

0.679

AC:

1435

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1586

3173

4759

6346

7932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<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:

0.644

Hom.:

25954

Bravo

AF:

0.712

Asia WGS

AF:

0.763

AC:

2653

AN:

3478

EpiCase

AF:

0.611

EpiControl

AF:

0.604

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1956T>C (p.Tyr652Tyr) variant in KCNH2 is classified as benign because it has been found in 67% (186322/279284) of chromosomes, including 63675 homozygotes, by the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-150648198-A-G). -

May 31, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 12, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Long QT syndrome 2

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Long QT syndrome

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: 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. -

Cardiac arrhythmia

Benign:1

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.2

(source)

DANN

Benign

0.50

PhyloP100

-0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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