rs199473648

Positions:

chr21-34370507-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000290310.4(KCNE2):c.29C>T(p.Thr10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,002 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T10A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

KCNE2
ENST00000290310.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5O:1

Conservation

PhyloP100: 0.894

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNE2	NM_172201.2 linkuse as main transcript	c.29C>T	p.Thr10Met	missense_variant	2/2	ENST00000290310.4	NP_751951.1
LOC105372791	XR_937683.3 linkuse as main transcript			downstream_gene_variant
LOC105372791	XR_007067848.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4 linkuse as main transcript	c.29C>T	p.Thr10Met	missense_variant	2/2	1	NM_172201.2	ENSP00000290310	P1
	ENST00000440403.2 linkuse as main transcript	n.782G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00605

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:

0.000478

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251330

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000226

AC:

331

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00406

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000250

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000522

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The Thr10Met variant in KCNE2 has previously been reported in 2 individuals with Long QT syndrome; however, in one family this variant was also identified in a 76 year-old relative who had coronary artery disease, congestive heart failure, and hypertension, but a normal ECG (Tester 2005, Gordon 2008). Functional studies have shown that the Thr10Met variant moderately impacts protein function (Gordon 2008); however, this in vitro assay may not accurately represent biological function. Whether KCNE2 variants alone cause Long QT syndrome or only confer increased risk when combined with other risk alleles is currently unclear. In summary, there is insufficient evidence for pathogenicity of this variant, and additional studies are needed to fully assess its clinical significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	See Variant Classification Assertion Criteria. -

Long QT syndrome 6

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are proposed mechanisms of disease in this gene and are associated with long QT syndrome 6 (MIM#613693) and familial atrial fibrillation (MIM#611493), respectively. However, this should be interpreted with caution as the gene-disease association for KCNE2 is currently unclear (PMIDs: 22166675, 26123744, 24796621, 28794082, 15368194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v2) (66 heterozygotes, 0 homozygotes) with a subpopulation frequency of 0.003 in the Ashkenazi Jewish population. (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.T10K variant has previously been reported in a patient with atrial fibrillation (PMID: 29805884). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. Although this variant has been identified in individuals with long QT syndrome and sudden unexplained death, it has more recently been re-classified as either a variant of uncertain significance or a likely benign variant (PMIDs: 18006462, 22677073, 28600387, 28794082, 32268277; ClinVar). (I) 1010 - Functional evidence for this variant is inconclusive. Patch clamp analysis in CHO cells demonstrated mild changes in the Ikr ventricular repolarization current when expressed in heterozygous state however the reliablity of this assay is questionable. Moreover, the use of CHO cells might not reflect the correct environment for testing a cardiac-related response (PMID: 18006462). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 05, 2019

Variant summary: KCNE2 c.29C>T (p.Thr10Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251330 control chromosomes (gnomAD). The observed variant frequency is approximately 4-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 benign. c.29C>T has been reported in the literature in individuals affected with long QT syndrome and Brugada syndrome and also, in individuals with sudden unexplained deaths (e.g. Burashnikov_2010, Burns_2016, Christiansen_2016, Lieve_2013, Mellor_2017, Tester_2012). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In at least two studies presenting patients affected with long QT syndrome (Roberts_2017) and a patient affected with auditory stimulus-induced long QT syndrome (Gordon_2008), the variant was detected in affected probands but it was also detected in their asymptomatic family members and therefore, appeared to not segregate with disease. Furthermore, Gordon et al (2008) carried out functional assessment of the variant through usage of whole-cell voltage clamp of transfected Chinese Hamster ovary cells and showed baseline IKr current reduction and slower recovery from inactivation for T10M-MiRP1-hERG channels when compared with wild-type channels, however only mild changes in IKr when KCNE2-Thr10Met was co-expressed with wild-type KCNH2. At least two co-occurrences with other pathogenic variants have been reported (PKP2 c.397C>T, p.Q133* (internal testing) and KCNQ1 c.1781G>A, p.Arg594Gln (Roberts_2017)), providing supporting evidence for a benign outcome for this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and as likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy;C0023976:Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Nov 21, 2018

The KCNE2 Thr10Met variant has been previously reported in probands with Long QT syndrome (Tester DJ, et al., 2005; Gordon E, et al., 2008; Lieve KV, et al., 2013). We have identified this variant in 2 probands. The first proband is of north-west European descent, has HCM and a second likely pathogenic variant in MYL2. Our second patient is of Ashkenazi Jewish descent and has a clinical diagnosis of long QT syndrome. The variant has been identified 63 times in the Genome Aggregation Database (MAF=0.0002; http://gnomad.broadinstitute.org/) and the Ashkenazi Jewish sub-population frequency is 0.0037, which is far higher than expected based on the prevalence of LQTS. In silico tools SIFT and PolyPhen2 predict this variant to be deleterious, but MutationTaster predicts it to be a 'polymorphism'. In summary based on the high allele frequency in the general population we classify KCNE2 Thr10Met as 'benign'. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 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:15840476;PMID:18006462). 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

0.10

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.027

MetaSVM

Uncertain

0.022

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.54

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0070

Polyphen

0.95

Vest4

0.11

MVP

0.94

MPC

0.12

ClinPred

0.040

GERP RS

4.7

Varity_R

0.063

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: -1

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