chr21-34449388-C-T

Position:

chr21-34449388-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000219.6(KCNE1):c.247G>A(p.Glu83Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,460,276 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E83T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000042 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 1.34

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.247G>A	p.Glu83Lys	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.247G>A	p.Glu83Lys	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000416

AC:

AN:

144174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000229

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000614

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251428

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1460276

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726520

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000416

AC:

AN:

144284

Hom.:

Cov.:

AF XY:

0.0000714

AC XY:

AN XY:

70028

show subpopulations

Gnomad4 AFR

AF:

0.0000254

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000230

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000614

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 19716085, 26159999, 26410412, 34426522) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in small number of probands; ExAC: 1/11570 Latino; ClinVar: 1 P (lit only) -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 83 of the KCNE1 protein (p.Glu83Lys). This variant is present in population databases (rs199473360, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KCNE1-related conditions (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 132673). 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The p.E83K variant (also known as c.247G>A) is located in coding exon 1 of the KCNE1 gene. This alteration results from a G to A substitution at nucleotide position 247. The glutamic acid at codon 83 is replaced by lysine, an amino acid with similar properties. In a study of long QT syndrome clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This alteration was also reported in an individual from a healthy exome cohort with a normal QTc interval, but additional clinical information was not available (Ghouse J et al. Eur. Heart J., 2015 Oct;36:2523-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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:19716085). 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

0.17

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

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

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.43

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

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

0.93

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

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

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

REVEL

Pathogenic

0.65

Sift

Benign

0.14

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

Sift4G

Benign

0.19

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

Polyphen

0.81

P;P;P;P;P;P;P;P

Vest4

0.53

MVP

0.89

MPC

0.32

ClinPred

0.15

GERP RS

2.1

Varity_R

0.14

gMVP

0.69

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

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