7-150948446-T-G

Variant names:

• chr7-150948446-T-G
• rs1805123
• NM_000238.4:c.2690A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000238.4(KCNH2):​c.2690A>C​(p.Lys897Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,097,454 control chromosomes in the GnomAD database, including 40,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K897R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (2640 hom., cov: 27)
  • Exomes 𝑓: 0.32 (37449 hom.)
• Consequence: KCNH2 NM_000238.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001136
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 2.77
• Publications: 207 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 -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014851391).
• BP6: Variant 7-150948446-T-G is Benign according to our data. Variant chr7-150948446-T-G is described in ClinVar as Benign. ClinVar VariationId is 67427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 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.2690A>C	p.Lys897Thr	missense splice_region	Exon 11 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2402A>C	p.Lys801Thr	missense splice_region	Exon 9 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.1670A>C	p.Lys557Thr	missense splice_region	Exon 7 of 11	NP_742054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2690A>C	p.Lys897Thr	missense splice_region	Exon 11 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1670A>C	p.Lys557Thr	missense splice_region	Exon 7 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2624A>C	p.Lys875Thr	missense splice_region	Exon 11 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 24594 AN: 116886 Hom.: 2636 Cov.: 27

Gnomad AFR AF: 0.0586

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0729

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.181 AC: 43182 AN: 238268 AF XY: 0.191

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0477

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.325 AC: 318343 AN: 980560 Hom.: 37449 Cov.: 28 AF XY: 0.320 AC XY: 159155 AN XY: 497778

African (AFR) AF: 0.0631 AC: 1144 AN: 18118

American (AMR) AF: 0.139 AC: 5295 AN: 37986

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 5310 AN: 17970

East Asian (EAS) AF: 0.109 AC: 1786 AN: 16328

South Asian (SAS) AF: 0.233 AC: 17350 AN: 74426

European-Finnish (FIN) AF: 0.252 AC: 7641 AN: 30272

Middle Eastern (MID) AF: 0.283 AC: 1227 AN: 4332

European-Non Finnish (NFE) AF: 0.359 AC: 266219 AN: 742380

Other (OTH) AF: 0.319 AC: 12371 AN: 38748

GnomAD4 genome AF: 0.210 AC: 24588 AN: 116894 Hom.: 2640 Cov.: 27 AF XY: 0.208 AC XY: 11756 AN XY: 56486

African (AFR) AF: 0.0586 AC: 1698 AN: 28986

American (AMR) AF: 0.211 AC: 2441 AN: 11596

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 677 AN: 2948

East Asian (EAS) AF: 0.0727 AC: 245 AN: 3368

South Asian (SAS) AF: 0.266 AC: 973 AN: 3664

European-Finnish (FIN) AF: 0.256 AC: 1646 AN: 6432

Middle Eastern (MID) AF: 0.274 AC: 63 AN: 230

European-Non Finnish (NFE) AF: 0.283 AC: 16237 AN: 57310

Other (OTH) AF: 0.229 AC: 377 AN: 1644

Alfa AF: 0.210 Hom.: 11563

Bravo AF: 0.155

TwinsUK AF: 0.247 AC: 917

ALSPAC AF: 0.242 AC: 933

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.233 AC: 2000

ExAC AF: 0.180 AC: 21831

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

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: Frequency in ESP (all): 2199/13006=16.9%

Sep 16, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Lys897Thr Yang et al (2002) observed the p.Lys897Thr variant in KCNH2 in 20% of drug-induced long QT cases and controls. 12-24% of individuals in the general population have this variant. In different studies of genetic variants associated with QT length variability in the general population (i.e. not long QT syndrome) p.Lys897Thr has been associated with both prolongation (Pfeufer et al 2005, Paavonen et al 2003, Newton-Cheh et al 2007) and shortening (Laitinen et al 2000, Bezzina et al 2003, Marjamaa et al 2009) of the QT interval.

Clinical Genetics, Academic 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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4 Other:1

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20215044, 19019189, 28336205, 31557540, 31522018, 29874175, 18222980, 14499861, 20181576, 26846766, 27153395, 16472284, 10862094, 23303164, 26109178, 22949429, 18791070, 22338672, 16116052, 21164565, 24388587, 12829173, 21831960, 14975928)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:10807545;PMID:11997281;PMID:12402336;PMID:12829173;PMID:14661677;PMID:14760488;PMID:15599693;PMID:16116052;PMID:16132053;PMID:16487223;PMID:17161064;PMID:17210839;PMID:18060054;PMID:18222980;PMID:18808722;PMID:19841300).

Long QT syndrome 2 Benign:2

Mar 06, 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

Long QT syndrome Benign:2

Oct 03, 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

Atrial fibrillation Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Cardiovascular phenotype Benign:1

May 08, 2019

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.

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

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiac arrhythmia Benign:1

Mar 09, 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.46
Sift	Benign	0.23	T
Sift4G	Benign	0.22	T
Polyphen		0.25	B
Vest4		0.53
MPC		0.20
ClinPred		0.013	T
GERP RS		-0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.084
gMVP		0.79
Mutation Taster		=45/55	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.0		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: rs1805123; hg19: chr7-150645534; COSMIC: COSV51125898; COSMIC: COSV51125898;