21-34449472-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_000219.6(KCNE1):​c.163G>A​(p.Gly55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,202,928 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.000048 ( 0 hom., cov: 16)
Exomes 𝑓: 0.000063 ( 4 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:2

Conservation

PhyloP100: 3.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a transmembrane_region Helical (size 22) in uniprot entity KCNE1_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_000219.6
BP4
Computational evidence support a benign effect (MetaRNN=0.30607957).
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNE1NM_000219.6 linkc.163G>A p.Gly55Ser 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
KCNE1ENST00000399286.3 linkc.163G>A p.Gly55Ser missense_variant Exon 4 of 4 1 NM_000219.6 ENSP00000382226.2 P15382

Frequencies

GnomAD3 genomes
AF:
0.0000482
AC:
5
AN:
103632
Hom.:
0
Cov.:
16
show subpopulations
Gnomad AFR
AF:
0.000114
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000335
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000208
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251428
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.000523
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000628
AC:
69
AN:
1099208
Hom.:
4
Cov.:
21
AF XY:
0.0000806
AC XY:
45
AN XY:
557970
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000483
Gnomad4 ASJ exome
AF:
0.0000430
Gnomad4 EAS exome
AF:
0.0000830
Gnomad4 SAS exome
AF:
0.000432
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000328
Gnomad4 OTH exome
AF:
0.0000208
GnomAD4 genome
AF:
0.0000482
AC:
5
AN:
103720
Hom.:
0
Cov.:
16
AF XY:
0.00
AC XY:
0
AN XY:
50074
show subpopulations
Gnomad4 AFR
AF:
0.000113
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000336
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000208
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000820
Hom.:
0
ExAC
AF:
0.000132
AC:
16
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Dec 01, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported in one individual referred for LQTS genetic testing (Kapplinger et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000549147.3, SCV000198416.4; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24710009, 19716085, 31941373, 28988457) -

Jan 12, 2018
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Variant KCNE1 p.Gly55Ser (c.163G>A) exon 4 (NM_000219.5, hg19 chr21-35821770-C-T) SCICD classification variant of uncertain significance, probably benign We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: too high MAF. (rs199473644, ExAC 0.07%)" 0.05198% MAF in South Asians -

not specified Uncertain:1
Feb 10, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Gly55Ser varian t in KCNE1 has not been previously reported in any individuals with hearing loss and was absent from large population studies. However, this variant has been re ported in one individual with long QT syndrome (Kapplinger 2009). The glycine (G ly) residue at position 55 is not conserved across several species including two mammals (hamster and mole) having serine (Ser) at this position, suggesting tha t the variant may be tolerated. However, this information is not sufficient to r ule out pathogenicity. In summary, the clinical significance of this variant can not be determined with certainty; however based upon the conservation data, we w ould lean towards a more likely benign role. -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1
Sep 08, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1
Oct 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 55 of the KCNE1 protein (p.Gly55Ser). This variant is present in population databases (rs199473644, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of LQTS (PMID: 19716085, 31941373). ClinVar contains an entry for this variant (Variation ID: 132657). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNE1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 17545244). 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
Sep 14, 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. -

Long QT syndrome 5 Other:1
-
Roden Lab, Vanderbilt University Medical Center
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro

- -

Congenital long QT syndrome Other:1
-
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 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
0.13
D
BayesDel_noAF
Pathogenic
0.38
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;D;D;D;D;D;D;D
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.76
.;.;T;.;.;.;.;.
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.31
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.8
M;M;M;M;M;M;M;M
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.3
N;.;.;N;N;N;N;N
REVEL
Pathogenic
0.69
Sift
Benign
0.28
T;.;.;T;T;T;T;T
Sift4G
Benign
0.27
T;T;T;T;T;T;T;T
Polyphen
0.98
D;D;D;D;D;D;D;D
Vest4
0.43
MutPred
0.34
Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);
MVP
0.93
MPC
0.29
ClinPred
0.41
T
GERP RS
5.2
Varity_R
0.12
gMVP
0.64

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.

Other links and lift over

dbSNP: rs199473644; hg19: chr21-35821770; API