rs551056698

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4BS1BS2

The NM_000238.4(KCNH2):c.560_568delGCGCGGGCG(p.Gly187_Gly189del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,447,500 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 8 hom. )

Consequence

KCNH2
NM_000238.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 2.40

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 -6 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000238.4.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00262 (399/152010) while in subpopulation AFR AF= 0.00848 (352/41532). AF 95% confidence interval is 0.00775. There are 4 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 399 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.560_568delGCGCGGGCG	p.Gly187_Gly189del	disruptive_inframe_deletion	Exon 4 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.560_568delGCGCGGGCG	p.Gly187_Gly189del	disruptive_inframe_deletion	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000532957.5 link	n.783_791delGCGCGGGCG		non_coding_transcript_exon_variant	Exon 4 of 9	2
KCNH2	ENST00000684241.1 link	n.1393_1401delGCGCGGGCG		non_coding_transcript_exon_variant	Exon 2 of 13

Frequencies

GnomAD3 genomes

AF:

0.00263

AC:

399

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00850

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000339

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000879

AC:

AN:

63692

Hom.:

AF XY:

0.000964

AC XY:

AN XY:

37342

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.00115

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000885

Gnomad SAS exome

AF:

0.00151

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000394

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000525

AC:

680

AN:

1295490

Hom.:

AF XY:

0.000542

AC XY:

346

AN XY:

638402

show subpopulations

Gnomad4 AFR exome

AF:

0.00878

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000429

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.000786

GnomAD4 genome

AF:

0.00262

AC:

399

AN:

152010

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00848

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000339

Gnomad4 OTH

AF:

0.00190

Bravo

AF:

0.00294

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

May 01, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH2: BS1, BS2 -

Apr 08, 2022

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The KCNH2 c.560_568delGCGCGGGCG (p.Gly187_Gly189del) variant involves an in-frame deletion of 9 nucleotides. One in silico tool predicts a benign outcome for this variant, which was confirmed by an in vitro electrophysiology study (Mannikko_2010). This variant was found in 15/10674 control chromosomes at a frequency of 0.0014053, which is approximately 14 times the estimated maximal expected allele frequency of a pathogenic KCNH2 variant (0.0001), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple individuals without clinical information(Shimizu_2009, Goldenberg_2011, Itoh_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. One internal sample carries this variant and KCNQ1 c.502G>A (pathogenic). Taken together, this variant is classified as benign. -

not specified

Uncertain:1Benign:1

Nov 18, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Poor coverage; Reported in 4 probands; ExAC: 0.2% (12/6666) South Asian - does not pass filter -

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

Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH2 NM_000238.3 exon 4 p.Gly187_Gly189del (c.560_568delGCGCGGGCG):This variant has been reported in the literature in at least 2 individuals with arrhythmia (i.e. sudden cardiac death, Long QT syndrome) (Shimizu 2009 PMID:19926013, Novotny 2011 PMID:21410720). This variant is present in 0.8% (76/9382) of African alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad-old.broadinstitute.org/variant/7-150655494-GCGCCCGCGC-G). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID:200600). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame deletion of 3 amino acids at position 187 within a repetitive region and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Long QT syndrome 1

Benign:1

Mar 16, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The KCNH2 Gly187_Gly189del is a 9 bp in-frame deletion. We identified this variant in a proband with Long QT syndrome, and no family history of disease or SCD. This variant was present at high frequency in the 1000 genomes project (MAF= 0.0028; http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (MAF= 0.008; http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to be tolerated. In summary, based on high frequency in general populations and in silico tools predicting no affect on the protein, we classify the KCNH2 Gly187_Gly189del variant as "likely benign". -

Long QT syndrome 2

Benign:1

Oct 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 20, 2016

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: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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