rs76649554

Positions:

• chr7-150947630-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000238.4(KCNH2):​c.2941A>G​(p.Ser981Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,612,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S981S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6 O:1
• Conservation: PhyloP100: 2.38

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057671696).
• BP6: Variant 7-150947630-T-C is Benign according to our data. Variant chr7-150947630-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67454.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, not_provided=1}. Variant chr7-150947630-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 36 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2941A>G	p.Ser981Gly	missense_variant	12/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2941A>G	p.Ser981Gly	missense_variant	12/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1921A>G	p.Ser641Gly	missense_variant	8/11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3774A>G		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000269 AC: 66 AN: 244912 Hom.: 0 AF XY: 0.000270 AC XY: 36 AN XY: 133284

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000992

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1460346 Hom.: 0 Cov.: 36 AF XY: 0.000284 AC XY: 206 AN XY: 726430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000768

Gnomad4 FIN exome AF: 0.000359

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74450

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:19841300). -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	Observed in two individuals diagnosed with hypertrophic cardiomyopathy (Lopes et al., 2015) and one individual with a history of sudden unexplained death (Sanchez et al., 2016) in the published literature.; Identified in a cohort of ostensibly healthy control individuals (Kappa et al., 2009), a cohort of individuals who underwent exome sequencing who were not selected for cardiomyopathy, arrhythmia, or a family history of sudden cardiac death (Ng et al., 2013), and a cohort of individuals recruited for non-antiarrhythmic drug exposure phenotypes who underwent pharmacogenomic testing (Van Driest et al., 2016); Reported with conflicting interpretations of pathogenicity by other clinical laboratories in ClinVar (ClinVar Variant ID# 67454; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27930701, 22949429, 19841300, 22581653, 23861362, 26746457, 25351510) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 02, 2019

The KCNH2 c.2941A>G; p.Ser981Gly variant (rs76649554; ClinVar Variation ID: 67454) has been previously reported in two individuals included in a cohort of hypertrophic cardiomyopathy (HCM) patients (Lopes 2015). However, this variant has also been identified in several control cohorts (Kapa 2009, Giudicessi 2012, Ng 2013, Van Driest 2016), and is also found in the general population with an overall allele frequency of 0.03% (75/276,264 alleles) in the Genome Aggregation Database. The serine at codon 981 is moderately conserved (Alamut software v2.11) and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain. References: Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. Kapa et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. Van Driest SL et al. Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. JAMA. 2016 Jan 5;315(1):47-57. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.44	.;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.17	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.21	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0010	B;B
Vest4		0.21
MVP		0.97
MPC		0.55
ClinPred		0.046	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.59

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: rs76649554; hg19: chr7-150644718;