rs149338401

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_000219.6(KCNE1):c.206A>G(p.Lys69Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000382 in 1,570,944 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. K69N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.50

Publications

7 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 105 uncertain in NM_000219.6

BP4

Computational evidence support a benign effect (MetaRNN=0.11247495).

BP6

Variant 21-34449429-T-C is Benign according to our data. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662. Variant chr21-34449429-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 132662.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.206A>G	p.Lys69Arg	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 link	c.206A>G	p.Lys69Arg	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

136724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000705

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000740

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:

0.00

Gnomad OTH

AF:

0.000554

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251408

AF XY:

0.0000441

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000223

AC:

AN:

1434220

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

714862

show subpopulations

African (AFR)

AF:

0.000847

AC:

AN:

33044

American (AMR)

AF:

0.0000449

AC:

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.00

AC:

AN:

85666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087022

Other (OTH)

AF:

0.0000336

AC:

AN:

59500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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:

0.000205

AC:

AN:

136724

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

AN XY:

66114

show subpopulations

African (AFR)

AF:

0.000705

AC:

AN:

36854

American (AMR)

AF:

0.0000740

AC:

AN:

13518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3172

East Asian (EAS)

AF:

0.00

AC:

AN:

4402

South Asian (SAS)

AF:

0.00

AC:

AN:

4056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62336

Other (OTH)

AF:

0.000554

AC:

AN:

1804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000292

Hom.:

Bravo

AF:

0.000314

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1Other:1

Mar 16, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in one apparently healthy African American individual (Ackerman et al., 2003), and one individual from a cohort of individuals not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death, who underwent exome sequencing, however, follow-up cardiac evaluations for these published cases were not reported (Ng et al., 2013); Reported in ClinVar (ClinVar Variant ID# 132662; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14661677, 22581653, 25649125, 23861362, 22947121, 24710009) -

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:14661677). -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Long QT syndrome

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 15, 2022

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

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

D;D;D;D;D;D;D;D

Eigen

Benign

-0.10

Eigen_PC

Benign

0.0073

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.76

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

M_CAP

Benign

0.029

MetaRNN

Benign

0.11

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

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.1

M;M;M;M;M;M;M;M

PhyloP100

2.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

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

REVEL

Uncertain

0.54

Sift

Benign

0.34

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

Sift4G

Benign

0.16

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

Polyphen

0.14

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

Vest4

0.076

MVP

0.92

MPC

0.069

ClinPred

0.049

GERP RS

4.0

Varity_R

0.072

gMVP

0.61

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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