rs763754260
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000219.6(KCNE1):āc.123G>Cā(p.Lys41Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0 ( 0 hom., cov: 13)
Exomes š: 0.0000083 ( 3 hom. )
Failed GnomAD Quality Control
Consequence
KCNE1
NM_000219.6 missense
NM_000219.6 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: -0.625
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.20441586).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE1 | NM_000219.6 | c.123G>C | p.Lys41Asn | missense_variant | 4/4 | ENST00000399286.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE1 | ENST00000399286.3 | c.123G>C | p.Lys41Asn | missense_variant | 4/4 | 1 | NM_000219.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 81652Hom.: 0 Cov.: 13 FAILED QC
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251418Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000831 AC: 7AN: 842560Hom.: 3 Cov.: 21 AF XY: 0.0000167 AC XY: 7AN XY: 418858
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GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 81652Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0AN XY: 39866
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Mar 14, 2016 | This variant is present in population databases (rs763754260, ExAC 0.006%) but has not been reported in the literature in individuals with a KCNE1-related disease. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This sequence change replaces lysine with asparagine at codon 41 of the KCNE1 protein (p.Lys41Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 27, 2016 | The p.K41N variant (also known as c.123G>C), located in coding exon 1 of the KCNE1 gene, results from a G to C substitution at nucleotide position 123. The lysine at codon 41 is replaced by asparagine, an amino acid with similar properties. Based on data from ExAC, the C allele has an overall frequency less than 0.01% (1/106190), having been observed in 0.006% (1/164080) of South Asian alleles. This amino acid position is poorly conserved in available 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;T;T;T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;.;T;.;.;.;.;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;.;.;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
B;B;B;B;B;B;B;B
Vest4
MutPred
Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);Loss of ubiquitination at K41 (P = 0.0056);
MVP
MPC
0.087
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at