rs1805120

Positions:

• chr7-150952443-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000238.4(KCNH2):​c.1539C>T​(p.Phe513Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,613,742 control chromosomes in the GnomAD database, including 55,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5902 hom., cov: 33)
  • Exomes 𝑓: 0.24 (49433 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.68

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-150952443-G-A is Benign according to our data. Variant chr7-150952443-G-A is described in ClinVar as [Benign]. Clinvar id is 36428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150952443-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1539C>T	p.Phe513Phe	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.1539C>T	p.Phe513Phe	synonymous_variant	6/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39774 AN: 151974 Hom.: 5887 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.302 AC: 75720 AN: 250862 Hom.: 13481 AF XY: 0.296 AC XY: 40172 AN XY: 135618

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.656

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.244 AC: 355943 AN: 1461650 Hom.: 49433 Cov.: 39 AF XY: 0.246 AC XY: 178821 AN XY: 727136

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.325

Gnomad4 EAS exome AF: 0.680

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.262 AC: 39815 AN: 152092 Hom.: 5902 Cov.: 33 AF XY: 0.270 AC XY: 20108 AN XY: 74340

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.652

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.269

Alfa AF: 0.233 Hom.: 1974

Bravo AF: 0.267

Asia WGS AF: 0.451 AC: 1566 AN: 3478

EpiCase AF: 0.225

EpiControl AF: 0.219

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	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 10, 2019	- -
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	Phe513Phe 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 25.2% (1110/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1805120). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	Oct 01, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiac arrhythmia Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

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;Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.45
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805120; hg19: chr7-150649531; COSMIC: COSV100059241;