rs74315447

Positions:

chr21-34370639-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_172201.2(KCNE2):c.161T>C(p.Met54Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,106 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,risk factor (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:3U:3B:1O:2

Conservation

PhyloP100: 4.86

Variant links:

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]

KCNE2 links:

ENSG00000225555 (HGNC:):

ENSG00000225555 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1409319).

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE2	NM_172201.2 linkuse as main transcript	c.161T>C	p.Met54Thr	missense_variant	2/2	ENST00000290310.4	NP_751951.1	Q9Y6J6
LOC105372791	NR_188571.1 linkuse as main transcript	n.648A>G		non_coding_transcript_exon_variant	2/3
LOC105372791	NR_188572.1 linkuse as main transcript	n.648A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4 linkuse as main transcript	c.161T>C	p.Met54Thr	missense_variant	2/2	1	NM_172201.2	ENSP00000290310.2		Q9Y6J6
ENSG00000225555	ENST00000440403.2 linkuse as main transcript	n.650A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000262

AC:

AN:

251474

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000140

AC:

204

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00494

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000230

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000328

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:3Uncertain:3Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 6

Pathogenic:1Uncertain:1Other:1

risk factor, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Mar 17, 2018	This c.161T>C (p.Met54Thr) variant in the KCNE2 gene has been reported in patients with variable presentations such as arrythmias, sinus bradycardia and long QT syndrome [PMID 10219239, 19716085, 23631727]. This variant was first reported in a patient with atypical response to exercise with prolonged QTc intervals [PMID 10219239]. In vitro functional assays showed that the variant affect protein function [PMID 23631727, 20042375, 24569893]. This variant has been detected in 29 heterozygous individuals from Europe in the ExAC population database (http://exac.broadinstitute.org/variant/21-35742938-T-C). Methionine at amino acid position 54 of the KCNE2 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Met54Thr change to be deleterious. This variant is thus classified as a risk factor. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the KCNE2 protein (p.Met54Thr). This variant is present in population databases (rs74315447, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KCNE2-related conditions (PMID: 10219239, 23936059, 26159999, 31737537, 33626434). ClinVar contains an entry for this variant (Variation ID: 6053). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNE2 function (PMID: 19219384, 20042375, 23631727, 31235733). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 16, 1999	- -

KCNE2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The KCNE2 c.161T>C (p.Met54Thr) variant has been reported in at least four studies in individuals with long QT syndrome (LQTS), drug-induced LQTS, or sudden unexplained death (SUD), and is found in a heterozygous state in six individuals (Abbot et al. 1999; Sesti et al. 2000; Kapplinger et al. 2009; Wang et al. 2014). The p.Met54Thr variant was also identified in two of over 6100 presumed healthy individuals (Freudenberg-Hua et al. 2014; Ghouse et al. 2015). The p.Met54Thr variant was absent from over 2300 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies indicated that the p.Met54Thr variant causes a reduction in current density in the potassium ion channel (Abbot et al. 1999; Sesti et al. 2000; Wu et al. 2010). Based on the collective evidence, the p.Met54Thr variant is classified as likely pathogenic for KCNE2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2024

Multiple functional studies demonstrate that p.(M54T) has a significant effect on potassium ion channel function in the heart (PMID: 19219384, 10219239, 12923204, 20042375); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20042375, 24569893, 24631769, 25333069, 10984545, 24631775, 26159999, 12923204, 19716085, 22677073, 23631727, 26859003, 28316956, 28794082, 10219239, 22378279, 25637381, 18006462, 14760488, 29661707, 30123799, 34426522, 19219384, 32078429, 34930020, 31235733, 23936059, 33626434, 31737537, 34247280, 33324689, 31447099, 25351510, 35125083, 34709746, 31980526) -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lildballe Lab, Aarhus University Hospital

Mar 01, 2024

PM2(s), PP2(m), PP3(s), BP6(s) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2020

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. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:19716085;PMID:20042375;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.018

Polyphen

0.96

Vest4

0.84

MVP

0.86

MPC

0.36

ClinPred

0.18

GERP RS

5.7

Varity_R

0.75

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over