rs1402178514
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5
The NM_000219.6(KCNE1):āc.137A>Gā(p.Tyr46Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y46Y) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 14)
Exomes š: 0.0000010 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNE1
NM_000219.6 missense
NM_000219.6 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 3.88
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a transmembrane_region Helical (size 22) in uniprot entity KCNE1_HUMAN there are 19 pathogenic changes around while only 4 benign (83%) in NM_000219.6
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.881
PP5
?
Variant 21-34449498-T-C is Pathogenic according to our data. Variant chr21-34449498-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517181.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE1 | NM_000219.6 | c.137A>G | p.Tyr46Cys | missense_variant | 4/4 | ENST00000399286.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE1 | ENST00000399286.3 | c.137A>G | p.Tyr46Cys | missense_variant | 4/4 | 1 | NM_000219.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 14
GnomAD3 genomes
?
Cov.:
14
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000101 AC: 1AN: 988036Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 498238
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
988036
Hom.:
Cov.:
21
AF XY:
AC XY:
0
AN XY:
498238
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 14
GnomAD4 genome
?
Cov.:
14
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Mar 09, 2017 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 07, 2017 | The p.Tyr46Cys variant in KCNE1 has been identified by our laboratory in the hom ozygous state in 1 individual with clinical features of Jervell and Lange-Nielse n syndrome (JLNS) and segregated in an affected sibling. This variant has been identified in 1/3494 Finnish chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org). Computational prediction tools and conse rvation analyses suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic for autosomal recessive JLNS. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2023 | The p.Y46C variant (also known as c.137A>G), located in coding exon 1 of the KCNE1 gene, results from an A to G substitution at nucleotide position 137. The tyrosine at codon 46 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited (Roberts JD et al. Circulation, 2020 Feb;141:429-439). Limited functional studies have suggested this alteration may impact current amplitudes and pore conductance (Wang Y et al. J. Gen. Physiol., 2012 Dec;140:653-69). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D
Vest4
MutPred
Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);Loss of methylation at K41 (P = 0.0725);
MVP
MPC
0.48
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at