rs139544114

chr7-150959602-G-Achr7-150959602-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000238.4(KCNH2):c.442C>T(p.Arg148Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,614,080 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R148Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (7 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:13 O:1
• Conservation: PhyloP100: 2.88

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012147158).
• BS2: High AC in GnomAd at 98 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.442C>T	p.Arg148Trp	missense_variant	3/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.442C>T	p.Arg148Trp	missense_variant	3/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.665C>T		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1	n.1275C>T		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00122 AC: 307 AN: 250940 Hom.: 3 AF XY: 0.00110 AC XY: 149 AN XY: 135704

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000627

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000817 AC: 1195 AN: 1461808 Hom.: 7 Cov.: 32 AF XY: 0.000814 AC XY: 592 AN XY: 727206

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000511

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74458

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00156 Hom.: 4

Bravo AF: 0.000767

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00105 AC: 128

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	The R148W variant has been observed in 0.1% global alleles, including 1.6% of alleles from individuals of Ashkenazi Jewish ancestry and three individuals reported to be homozygous, in large population cohorts (Lek et al., 2016).; This variant is associated with the following publications: (PMID: 17088455, 19322600, 19841300, 20400443, 21410720, 22949429, 24055113, 23465283, 24334129, 25637381, 26159999, 27153395, 27875062, 27650965, 28988457, 31043699, 32048431) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KCNH2: BS1 -
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:19322600;PMID:19841300;PMID:21410720). -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Long QT syndrome Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PP2, PP3, BS1 -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 18, 2013	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.Arg148Trp Given the data reviewed below we also consider it a variant of uncertain significance. Millat et al (2009) observed the variant in a 4mo male SIDS case. Kapa et al (2009) report the variant as a polymorphism. They do not provide the frequency of the variant in controls but note that they considered something a polymorphism if it was seen more than once in the 1369 controls they studied. This same group reported the variant in a case of autopsy-negative sudden cardiac death but noted it was a "less common polymorphism" without functional data supporting pathogenicity. Novotny et al (2011) sequenced several long QT genes in individuals with coronary artery disease and ventricular fibrillation and observed this variant in one individual. Crotti et al (2012) reported the variant in one individual with long QT syndrome. No ancestry or segregation data were provided. The variant is in the N-terminal region of the protein. In total the variant has been seen in 25 of 7164 individuals in publicly available general population samples. The variant is listed in dbSNP (rs139544114), pointing to the NHLBI ESP data and also noting that ~9/661 individuals in the ClinSeq population from NIH (a general population cohort) were heterozygotes. The variant was reported online in 16 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 18th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	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: Multiple reports as VUS/polymorphism, ExAC: 0.1% (99/66588) European chromosomes -

Long QT syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Conduction disorder of the heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 27, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2017

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. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.012	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.84	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.95
MPC		1.0
ClinPred		0.044	T
GERP RS		3.8
Varity_R		0.23
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs139544114; hg19: chr7-150656690;