rs143011005

chr7-150951830-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000238.4(KCNH2):c.1563C>T(p.Ile521=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,572,678 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00087 (5 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -0.0400

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-150951830-G-A is Benign according to our data. Variant chr7-150951830-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 70633.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=9, Uncertain_significance=1}. Variant chr7-150951830-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000866 (1230/1420342) while in subpopulation MID AF= 0.00522 (29/5554). AF 95% confidence interval is 0.00373. There are 5 homozygotes in gnomad4_exome. There are 632 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High AC in GnomAd at 152 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1563C>T	p.Ile521=	synonymous_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1563C>T	p.Ile521=	synonymous_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000896

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00127 AC: 280 AN: 221210 Hom.: 3 AF XY: 0.00124 AC XY: 147 AN XY: 118378

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.000847

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.000866 AC: 1230 AN: 1420342 Hom.: 5 Cov.: 36 AF XY: 0.000903 AC XY: 632 AN XY: 700236

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00920

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000849

Gnomad4 FIN exome AF: 0.0000401

Gnomad4 NFE exome AF: 0.000661

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.00107 AC XY: 80 AN XY: 74494

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.00133

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KCNH2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2015	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Long QT syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Long QT syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 12, 2018

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2015

This alteration is classified as likely 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 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.7
Dann	Benign	0.71

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: rs143011005; hg19: chr7-150648918; COSMIC: COSV51167521;