chr21-34449529-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000219.6(KCNE1):​c.106C>G​(p.Arg36Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 11)

Consequence

KCNE1
NM_000219.6 missense

Scores

2
17

Clinical Significance

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

Conservation

PhyloP100: -2.44

Publications

3 publications found
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 Gene-Disease associations (from GenCC):
  • long QT syndrome 5
    Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Jervell and Lange-Nielsen syndrome 2
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
  • Jervell and Lange-Nielsen syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • atrial fibrillation
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05855933).
BP6
Variant 21-34449529-G-C is Benign according to our data. Variant chr21-34449529-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1429999.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNE1NM_000219.6 linkc.106C>G p.Arg36Gly 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.106C>G p.Arg36Gly missense_variant Exon 4 of 4 1 NM_000219.6 ENSP00000382226.2 P15382

Frequencies

GnomAD3 genomes
Cov.:
11
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251368
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
23
GnomAD4 genome
Cov.:
11
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Long QT syndrome Uncertain:1
Oct 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 36 of the KCNE1 protein (p.Arg36Gly). This variant is present in population databases (rs372398235, gnomAD 0.002%). 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: 1429999). 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%. 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
Jun 06, 2025
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
0.44
DANN
Benign
0.74
DEOGEN2
Uncertain
0.44
T;T;T;T;T;T;T;T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.45
.;.;T;.;.;.;.;.
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.059
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
-0.89
N;N;N;N;N;N;N;N
PhyloP100
-2.4
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.72
N;.;.;N;N;N;N;N
REVEL
Uncertain
0.33
Sift
Benign
0.40
T;.;.;T;T;T;T;T
Sift4G
Benign
0.36
T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;B;B;B;B
Vest4
0.035
MutPred
0.25
Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);
MVP
0.55
MPC
0.095
ClinPred
0.033
T
GERP RS
-5.1
Varity_R
0.058
gMVP
0.45
Mutation Taster
=89/11
polymorphism

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

Other links and lift over

dbSNP: rs372398235; hg19: chr21-35821827; API