21-34449496-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000219.6(KCNE1):c.139G>A(p.Val47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000794 in 1,083,708 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. V47G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000048 ( 1 hom., cov: 14)

Exomes 𝑓: 0.000082 ( 4 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.43

Publications

17 publications found

Variant links:

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KCNE1 Gene-Disease associations (from GenCC):

long QT syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Jervell and Lange-Nielsen syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 100 uncertain in NM_000219.6

BP4

Computational evidence support a benign effect (MetaRNN=0.01902014).

BP6

Variant 21-34449496-C-T is Benign according to our data. Variant chr21-34449496-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527065.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.139G>A	p.Val47Ile	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 link	c.139G>A	p.Val47Ile	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes

AF:

0.0000478

AC:

AN:

83714

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000217

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000287

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000278

AC:

AN:

251432

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000820

AC:

AN:

999994

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

504598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22580

American (AMR)

AF:

0.000730

AC:

AN:

38366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20864

East Asian (EAS)

AF:

0.0000314

AC:

AN:

31852

South Asian (SAS)

AF:

0.000280

AC:

AN:

67942

European-Finnish (FIN)

AF:

0.0000222

AC:

AN:

44950

Middle Eastern (MID)

AF:

0.000213

AC:

AN:

4698

European-Non Finnish (NFE)

AF:

0.0000400

AC:

AN:

725512

Other (OTH)

AF:

0.0000694

AC:

AN:

43230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000478

AC:

AN:

83714

Hom.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

40886

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19818

American (AMR)

AF:

0.000217

AC:

AN:

9204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1808

East Asian (EAS)

AF:

0.00

AC:

AN:

2308

South Asian (SAS)

AF:

0.00

AC:

AN:

2500

European-Finnish (FIN)

AF:

0.000287

AC:

AN:

6976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39376

Other (OTH)

AF:

0.00

AC:

AN:

1156

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000136

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 04, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 04, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 21907427, 30245029, 24710009, 28807990, 29309402, 33919104) -

not specified

Benign:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP4 -

Feb 08, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Mar 15, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 12, 2019

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

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.41

DEOGEN2

Uncertain

0.43

T;T;T;T;T;T;T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.64

.;.;T;.;.;.;.;.

M_CAP

Benign

0.043

MetaRNN

Benign

0.019

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

-0.95

N;N;N;N;N;N;N;N

PhyloP100

1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

0.48

N;.;.;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

1.0

T;.;.;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B;B

Vest4

0.23

MVP

0.65

MPC

0.062

ClinPred

0.0088

GERP RS

1.7

Varity_R

0.014

gMVP

0.45

Mutation Taster

=100/0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over