NM_000238.4:c.1692A>G

Variant names:

• chr7-150951701-T-C
• rs1805121
• NM_000238.4:c.1692A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000238.4(KCNH2):​c.1692A>G​(p.Leu564Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,944 control chromosomes in the GnomAD database, including 154,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22197 hom., cov: 36)
  • Exomes 𝑓: 0.41 (132576 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.05
• Publications: 26 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-150951701-T-C is Benign according to our data. Variant chr7-150951701-T-C is described in ClinVar as Benign. ClinVar VariationId is 200228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1692A>G	p.Leu564Leu	synonymous	Exon 7 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.1404A>G	p.Leu468Leu	synonymous	Exon 5 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.1692A>G	p.Leu564Leu	synonymous	Exon 7 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1692A>G	p.Leu564Leu	synonymous	Exon 7 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.672A>G	p.Leu224Leu	synonymous	Exon 3 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.990A>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77877 AN: 152126 Hom.: 22156 Cov.: 36

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.479 AC: 120387 AN: 251176 AF XY: 0.468

Gnomad AFR exome AF: 0.759

Gnomad AMR exome AF: 0.531

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.868

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.411 AC: 601273 AN: 1461700 Hom.: 132576 Cov.: 72 AF XY: 0.411 AC XY: 299172 AN XY: 727134

African (AFR) AF: 0.761 AC: 25490 AN: 33480

American (AMR) AF: 0.522 AC: 23359 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 10379 AN: 26136

East Asian (EAS) AF: 0.896 AC: 35565 AN: 39696

South Asian (SAS) AF: 0.471 AC: 40612 AN: 86252

European-Finnish (FIN) AF: 0.467 AC: 24915 AN: 53366

Middle Eastern (MID) AF: 0.419 AC: 2415 AN: 5764

European-Non Finnish (NFE) AF: 0.371 AC: 412020 AN: 1111908

Other (OTH) AF: 0.439 AC: 26518 AN: 60390

GnomAD4 genome AF: 0.512 AC: 77979 AN: 152244 Hom.: 22197 Cov.: 36 AF XY: 0.518 AC XY: 38533 AN XY: 74436

African (AFR) AF: 0.742 AC: 30815 AN: 41536

American (AMR) AF: 0.481 AC: 7356 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1441 AN: 3472

East Asian (EAS) AF: 0.861 AC: 4458 AN: 5176

South Asian (SAS) AF: 0.467 AC: 2254 AN: 4828

European-Finnish (FIN) AF: 0.480 AC: 5088 AN: 10602

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25108 AN: 68002

Other (OTH) AF: 0.477 AC: 1009 AN: 2114

Alfa AF: 0.440 Hom.: 7666

Bravo AF: 0.527

Asia WGS AF: 0.627 AC: 2180 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.360

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Nov 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu564Leu in exon 7 of KCNH2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 87% (16383/18860) o f East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs1805121).

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

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

Jul 10, 2011

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

Long QT syndrome Benign:3

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Long QT syndrome 2 Benign:2

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.

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Apr 20, 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

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 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.62
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1805121; hg19: chr7-150648789; COSMIC: COSV51125910;