rs149338401

Positions:

chr21-34449429-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS1

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).

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:2B:2O:1

Conservation

PhyloP100: 2.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a helix (size 25) in uniprot entity KCNE1_HUMAN there are 16 pathogenic changes around while only 5 benign (76%) 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132662.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=2, Uncertain_significance=2}. Variant chr21-34449429-T-C is described in Lovd as [Benign]. Variant chr21-34449429-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000205 (28/136724) while in subpopulation AFR AF= 0.000705 (26/36854). AF 95% confidence interval is 0.000493. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 17. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.206A>G	p.Lys69Arg	missense_variant	4/4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.206A>G	p.Lys69Arg	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

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

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251408

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135906

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 SAS 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

Gnomad4 AFR exome

AF:

0.000847

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.000205

AC:

AN:

136724

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

AN XY:

66114

show subpopulations

Gnomad4 AFR

AF:

0.000705

Gnomad4 AMR

AF:

0.0000740

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000554

Alfa

AF:

0.000200

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:2Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	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) -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:14661677). -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 69 of the KCNE1 protein (p.Lys69Arg). This variant is present in population databases (rs149338401, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 132662). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

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

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

MutationTaster

Benign

0.69

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

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

0.096

gMVP

0.61

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

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