7-150951110-A-G

Position:

• chr7-150951110-A-G

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.1956T>C​(p.Tyr652Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,608,930 control chromosomes in the GnomAD database, including 331,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38734 hom., cov: 34)
  • Exomes 𝑓: 0.63 (292885 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.277

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=-0.72).
• BP6: Variant 7-150951110-A-G is Benign according to our data. Variant chr7-150951110-A-G is described in ClinVar as [Benign]. Clinvar id is 200230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951110-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.277 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1956T>C	p.Tyr652Tyr	synonymous_variant	8/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1956T>C	p.Tyr652Tyr	synonymous_variant	8/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106660 AN: 152070 Hom.: 38677 Cov.: 34

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.898

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.674

GnomAD3 exomes AF: 0.663 AC: 164327 AN: 247964 Hom.: 55682 AF XY: 0.658 AC XY: 88305 AN XY: 134152

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.907

Gnomad SAS exome AF: 0.669

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.630 AC: 917867 AN: 1456742 Hom.: 292885 Cov.: 53 AF XY: 0.631 AC XY: 456738 AN XY: 724184

Gnomad4 AFR exome AF: 0.901

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.608

Gnomad4 EAS exome AF: 0.910

Gnomad4 SAS exome AF: 0.671

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.649

GnomAD4 genome AF: 0.702 AC: 106780 AN: 152188 Hom.: 38734 Cov.: 34 AF XY: 0.704 AC XY: 52384 AN XY: 74380

Gnomad4 AFR AF: 0.886

Gnomad4 AMR AF: 0.654

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.898

Gnomad4 SAS AF: 0.669

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.604

Gnomad4 OTH AF: 0.679

Alfa AF: 0.636 Hom.: 13341

Bravo AF: 0.712

Asia WGS AF: 0.763 AC: 2653 AN: 3478

EpiCase AF: 0.611

EpiControl AF: 0.604

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 05, 2019	The c.1956T>C (p.Tyr652Tyr) variant in KCNH2 is classified as benign because it has been found in 67% (186322/279284) of chromosomes, including 63675 homozygotes, by the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-150648198-A-G). -
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	PreventionGenetics, part of Exact Sciences	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2012	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, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 31, 2020	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -

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. -

Long QT syndrome Benign:2

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	- -

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 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1137617; hg19: chr7-150648198; COSMIC: COSV51214965;