rs740952

Positions:

• chr7-150952515-G-A
• chr7-150952515-G-C
• chr7-150952515-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000238.4(KCNH2):​c.1467C>T​(p.Ile489=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,613,896 control chromosomes in the GnomAD database, including 55,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5975 hom., cov: 32)
  • Exomes 𝑓: 0.24 (49502 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.955

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-150952515-G-A is Benign according to our data. Variant chr7-150952515-G-A is described in ClinVar as [Benign]. Clinvar id is 255614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150952515-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.955 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1467C>T	p.Ile489=	synonymous_variant	6/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1467C>T	p.Ile489=	synonymous_variant	6/15	1	NM_000238.4	ENSP00000262186	P1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40214 AN: 151916 Hom.: 5956 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.303 AC: 76066 AN: 251404 Hom.: 13554 AF XY: 0.297 AC XY: 40296 AN XY: 135890

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.651

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.244 AC: 356834 AN: 1461862 Hom.: 49502 Cov.: 40 AF XY: 0.246 AC XY: 179247 AN XY: 727236

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.399

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.673

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.265 AC: 40263 AN: 152034 Hom.: 5975 Cov.: 32 AF XY: 0.273 AC XY: 20268 AN XY: 74290

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.270

Alfa AF: 0.229 Hom.: 7987

Bravo AF: 0.272

Asia WGS AF: 0.449 AC: 1558 AN: 3478

EpiCase AF: 0.226

EpiControl AF: 0.220

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2016	Ile489Ile in exon 6 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 26.3% (1158/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs740952). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 19, 2020	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Long QT syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Long QT syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene -

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
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.9
DANN	Benign	0.88

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

LitVar

Other links and lift over

dbSNP: rs740952; hg19: chr7-150649603; COSMIC: COSV100059245;