rs142153692

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_172201.2(KCNE2):c.40G>A(p.Val14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,166 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. V14D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:6O:1

Conservation

PhyloP100: 1.77

Publications

11 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009433717).

BP6

Variant 21-34370518-G-A is Benign according to our data. Variant chr21-34370518-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 67621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNE2	NM_172201.2 link	c.40G>A	p.Val14Ile	missense_variant	Exon 2 of 2	ENST00000290310.4	NP_751951.1
LOC105372791	NR_188571.1 link	n.769C>T		non_coding_transcript_exon_variant	Exon 2 of 3
LOC105372791	NR_188572.1 link	n.769C>T		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.40G>A	p.Val14Ile	missense_variant	Exon 2 of 2	1	NM_172201.2	ENSP00000290310.2

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000187

AC:

AN:

251384

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000158

AC:

231

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000135

AC:

150

AN:

1112004

Other (OTH)

AF:

0.000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000525

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000239

Hom.:

Bravo

AF:

0.000703

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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:19716085). -

Sep 24, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24055113, 28988457, 23465283, 25637381, 19716085, 15913580, 31043699) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Long QT syndrome 6

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Cardiovascular phenotype

Benign:1

May 31, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.5

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.24

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.52

M_CAP

Benign

0.046

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

PhyloP100

1.8

PrimateAI

Benign

0.30

PROVEAN

Benign

0.0

REVEL

Benign

0.23

Sift

Benign

0.44

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.052

MVP

0.66

MPC

0.085

ClinPred

0.011

GERP RS

4.7

Varity_R

0.031

gMVP

0.76

Mutation Taster

=87/13

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