rs146614850

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PS1BP4_Moderate

The NM_000219.6(KCNE1):c.273C>G(p.Asp91Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,457,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.83

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 2 ACMG points.

PS1

Transcript NM_000219.6 (KCNE1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

BP4

Computational evidence support a benign effect (MetaRNN=0.19269595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.273C>G	p.Asp91Glu	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.273C>G	p.Asp91Glu	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143850

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000308

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251456

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1457924

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725442

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000139

AC:

AN:

143850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69738

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000308

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 91 of the KCNE1 protein (p.Asp91Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 24217263). ClinVar contains an entry for this variant (Variation ID: 427969). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Apr 30, 2017

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2019

The p.D91E variant (also known as c.273C>G), located in coding exon 1 of the KCNE1 gene, results from a C to G substitution at nucleotide position 273. The aspartic acid at codon 91 is replaced by glutamic acid, an amino acid with highly similar properties. This variant co-occurred with a KCNQ1 mutation in an individual from a long QT syndrome cohort (Hedley PL et al. Cardiovasc J Afr, 2013 Jul;24:231-7). This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.69

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.62

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

M_CAP

Benign

0.034

MetaRNN

Benign

0.19

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

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

0.97

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

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.68

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

REVEL

Uncertain

0.40

Sift

Benign

0.18

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

Sift4G

Benign

0.39

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

Polyphen

0.015

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

Vest4

0.092

MutPred

0.26

Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);Gain of methylation at K90 (P = 0.0871);

MVP

0.90

MPC

0.28

ClinPred

0.63

GERP RS

4.9

Varity_R

0.065

gMVP

0.49

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