chr21-34449529-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBP6BS2

The NM_000219.6(KCNE1):​c.106C>T​(p.Arg36Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R36H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000050 ( 2 hom., cov: 11)
Exomes 𝑓: 0.0000083 ( 3 hom. )
Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

5
14

Clinical Significance

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

Conservation

PhyloP100: -2.44
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 -5 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-34449528-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.24819806).
BP6
Variant 21-34449529-G-A is Benign according to our data. Variant chr21-34449529-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 518804.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNE1NM_000219.6 linkuse as main transcriptc.106C>T p.Arg36Cys missense_variant 4/4 ENST00000399286.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNE1ENST00000399286.3 linkuse as main transcriptc.106C>T p.Arg36Cys missense_variant 4/41 NM_000219.6 P1

Frequencies

GnomAD3 genomes
AF:
0.0000496
AC:
4
AN:
80572
Hom.:
2
Cov.:
11
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000225
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:
0.0000522
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251368
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000827
AC:
7
AN:
845936
Hom.:
3
Cov.:
23
AF XY:
0.00000238
AC XY:
1
AN XY:
420738
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000698
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:
0.00000773
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000496
AC:
4
AN:
80572
Hom.:
2
Cov.:
11
AF XY:
0.00
AC XY:
0
AN XY:
39312
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000225
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000522
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000301
Hom.:
0
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 07, 2024Observed in a patient with hypertrophic cardiomyopathy in published literature; the patient harbored variants in other genes (PMID: 23396983); Functional studies indicate position R36 is involved in contact with position Q147 of the KCNQ1 gene; the exact consequences of the R36C variant cannot be determined from this study (PMID: 21152909); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16414944, 21152909, 23396983) -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 30, 2023In 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNE1 protein function. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 36 of the KCNE1 protein (p.Arg36Cys). This variant is present in population databases (rs372398235, gnomAD 0.007%). ClinVar contains an entry for this variant (Variation ID: 518804). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 28, 2024This 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
0.10
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
9.3
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;D;D;D;D;D;D;D
Eigen
Benign
-0.88
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.73
.;.;T;.;.;.;.;.
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.25
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Benign
0.90
L;L;L;L;L;L;L;L
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-1.9
N;.;.;N;N;N;N;N
REVEL
Uncertain
0.50
Sift
Benign
0.054
T;.;.;T;T;T;T;T
Sift4G
Benign
0.064
T;T;T;T;T;T;T;T
Polyphen
0.85
P;P;P;P;P;P;P;P
Vest4
0.12
MVP
0.79
MPC
0.31
ClinPred
0.11
T
GERP RS
-5.1
Varity_R
0.066
gMVP
0.50

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.

Other links and lift over

dbSNP: rs372398235; hg19: chr21-35821827; COSMIC: COSV100492419; API