21-34370503-C-G

Position:

• chr21-34370503-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_172201.2(KCNE2):​c.25C>G​(p.Gln9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,614,182 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (8 hom.)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:2
• Conservation: PhyloP100: 1.25

Genes affected

KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 21-34370503-C-G is Benign according to our data. Variant chr21-34370503-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 6052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-34370503-C-G is described in Lovd as [Benign]. Variant chr21-34370503-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000494 (722/1461890) while in subpopulation AFR AF= 0.0177 (591/33480). AF 95% confidence interval is 0.0165. There are 8 homozygotes in gnomad4_exome. There are 310 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 652 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE2	NM_172201.2	c.25C>G	p.Gln9Glu	missense_variant	2/2	ENST00000290310.4
LOC105372791	XR_937683.3			downstream_gene_variant
LOC105372791	XR_007067848.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE2	ENST00000290310.4	c.25C>G	p.Gln9Glu	missense_variant	2/2	1	NM_172201.2	P1
	ENST00000440403.2	n.786G>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152174 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00114 AC: 287 AN: 251328 Hom.: 3 AF XY: 0.000839 AC XY: 114 AN XY: 135884

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461890 Hom.: 8 Cov.: 31 AF XY: 0.000426 AC XY: 310 AN XY: 727248

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152292 Hom.: 8 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74474

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.00485

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 22581653, 14661677, 14760488, 20981092, 10219239, 17210839, 31043699, 32145446) -
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:10219239;PMID:14661677;PMID:14760488;PMID:17210839;PMID:20981092). -

Long QT syndrome 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2018

Variant summary: KCNE2 c.25C>G (p.Gln9Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 281062 control chromosomes, predominantly at a frequency of 0.017 within the African subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 243 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE2 causing Arrhythmia phenotype (7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Co-occurrences with other pathogenic variant(s) have been reported in an internal sample (KSNH2 c.1841C>T, p.A614V), providing supporting evidence for a benign role. The variant, c.25C>G, has been reported in the literature in individuals affected with SIDS (Arnestad_2007) and also in an African American patient that developed QTc prolongation, torsades de pointes (TdP), and ventricular fibrillation after administration of macrolides (Abbott_1999). Functional studies demonstrated that this variant slightly impairs channel function (Lu_2003, Perlstein_2005) and increases the potency of clarithromycin as a hERG channel blocker (Abbott_1999). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia in healthy individuals but suggest that patients with cardiomyopathies carrying this variant may develop macrolide-induced arrhythmia. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign until large scale case control studies will be available. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2015

This alteration is classified as 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. -

Atrial fibrillation, familial, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Long QT syndrome 6, acquired, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.23
Sift	Benign	0.26	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.65
MVP		0.82
MPC		0.12
ClinPred		0.0041	T
GERP RS		4.6
Varity_R		0.088
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16991652; hg19: chr21-35742802;