rs74315448

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_172201.2(KCNE2):c.170T>C(p.Ile57Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000655 in 1,614,210 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I57M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 5 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:11O:1

Conservation

PhyloP100: 6.81

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
long QT syndrome 6
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNE2 links:

ENSG00000225555 (HGNC:):

ENSG00000225555 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32147172).

BP6

Variant 21-34370648-T-C is Benign according to our data. Variant chr21-34370648-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6054.

BS2

High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE2	NM_172201.2 link	c.170T>C	p.Ile57Thr	missense_variant	Exon 2 of 2	ENST00000290310.4	NP_751951.1	Q9Y6J6
LOC105372791	NR_188571.1 link	n.639A>G		non_coding_transcript_exon_variant	Exon 2 of 3
LOC105372791	NR_188572.1 link	n.639A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4 link	c.170T>C	p.Ile57Thr	missense_variant	Exon 2 of 2	1	NM_172201.2	ENSP00000290310.2		Q9Y6J6

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00105

AC:

265

AN:

251484

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.000651

AC:

951

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

523

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33480

American (AMR)

AF:

0.00188

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00109

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000480

AC:

534

AN:

1112008

Other (OTH)

AF:

0.00161

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152320

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41566

American (AMR)

AF:

0.00268

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68022

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000828

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 6

Pathogenic:1Uncertain:4Benign:2

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1. -

Jun 25, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 27, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Apr 16, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5Other:1

May 01, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The KCNE2 c.170T>C (p.Ile57Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense change of Ile57 which is located in a predicted transmembrane domain. 5/5 in silico tools predict a damaging outcome for this variant, and functional studies indicate that this variant compromises function: 1) I57T-hMiRP1 diminished potassium flux through MiRP1/HERG channel complexes (Abbott_Cell_1999), 2) KCNE2-I57T decreased the rate of activation of the KCNQ1 current, abolished the hump of the tail currents upon repolarization, accelerated the deactivation process (127ms vs 552ms for WT), and shifted the voltage dependency of the channel activation towards more depolarized potentials (Tinel_EMBO_200), and 3) KCNQ2+KCNE2-I57T had a significantly increased (227ms vs 156ms for WT) time constant of deactivation (no significant change in time constant of activation), while KCNQ2+KCNQ3+KCNE2-I57T significantly decreased (68.0ms vs 99.5ms for WT) the time constant of activation (no significant change in time constant of deactivation; Tinel_FEBS_2000). However the variant 1) did not reduce mean current density of hMiRP1-Kv2.1 channels, 2) had no significant effect on V1/2 activation (McCrossan_J Membr Biol_2009), and 3) had the same sensitivity to oxatomide as wild type, thus the variant did not alter sensitivity to drug inhibition (Sesti_PNAS_2000). Furthermore, it has not been established if these quantitative and qualitative functional observations are sufficient to induce arrhythmia in the absence of other precipitating factors; therefore, this variant may only be a risk allele. This variant was found in 107/125050 control chromosomes (including one homozygote) including ExAC at a frequency of 0.0008557, which is approximately 128 times the estimated maximal expected allele frequency of a pathogenic KCNE2 variant (0.0000067), suggesting this variant is likely a benign polymorphism.This variant has been reported in many patients with LQTS and two reports of patients with drug induced LQTS, but majority of reports in the literature do not provide co-segregation data. This variant was found to in one neonate with mild LQTS and his two relatives (including mother) in one family, however clinical data was only provided for the proband that had a QT interval of 462ms as a newborn, but had normal QTc at follow-up (Schwartz_Circ_2009). The variant was reported in a patient with LQTS and neonatal seizures who also carried another pathogenic variant SCN5A R1623Q and the unaffected father, brother, and sister did not carry this KCNE2 c.170T>C variant, suggesting that this variant was not causative in this family (Heron_Epilepsia_2010). In another family with 5 affected WolffParkinsonWhite (WPW) syndrome, this variant was found in only 2 affected and also in 4 unaffected family members; a pathogenic MYH6 variant was found to co-segregate with disease in this family as well, thus suggesting that KCNE2 c.170T>C was not causative in this family (Bowels_AJMG_2015). In addition, two patients with primary electrical disease also carried another VUS, ANK2 p.His931Gln and CACNB2 p.Ala340Thr, respectively (Proost_2017). The variant is reported with conflicting classifications from multiple clinical diagnostic laboratories or databases, with the most recent reports being VUS and likely benign (2016). Recently, this variant was observed in six homozygotes who did not express phenotype from Saudi Human Genome Program (Abouelhoda_GenomeBiology_2016). Taken together, this the variant was classified as likely benign. -

Nov 18, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22378279, 10219239, 24796621, 24144883, 24055113, 25637381, 19841298, 20042375, 16922724, 19716085, 23382499, 10984545, 25696450, 19863579, 26159999, 24606995, 23098067, 19862833, 11101505, 11034315, 28341588, 27595200, 27884173, 29672598, 29032884, 28794082, 30986657, 31019283, 31320904, 31737537, 30847666) -

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

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

This variant has been reported in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:16922724;PMID:19716085;PMID:20042375;PMID:22378279). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain:1Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

KCNE2-related disorder

Benign:1

Feb 24, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atrial fibrillation, familial, 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.32

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.4

PhyloP100

6.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.97

MVP

0.96

MPC

0.57

ClinPred

0.041

GERP RS

5.7

Varity_R

0.56

gMVP

0.88

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over