chr7-150951701-T-C

Position:

• chr7-150951701-T-C

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.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:15
• Conservation: PhyloP100: 2.05

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=-0.64).
• BP6: Variant 7-150951701-T-C is Benign according to our data. Variant chr7-150951701-T-C is described in ClinVar as [Benign]. Clinvar id is 200228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951701-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1692A>G	p.Leu564Leu	synonymous_variant	7/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1692A>G	p.Leu564Leu	synonymous_variant	7/15	1	NM_000238.4	ENSP00000262186.5

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

GnomAD3 exomes AF: 0.479 AC: 120387 AN: 251176 Hom.: 31870 AF XY: 0.468 AC XY: 63522 AN XY: 135818

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 SAS exome AF: 0.466

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

Gnomad4 AFR exome AF: 0.761

Gnomad4 AMR exome AF: 0.522

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.896

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.439

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

Gnomad4 AFR AF: 0.742

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.477

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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 02, 2017	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). -
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, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
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 02, 2024	- -

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 12, 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	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2015

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

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	-0.64
CADD	Benign	13
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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