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
Consequence
NM_000219.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE1 | NM_000219.6 | c.106C>T | p.Arg36Cys | missense_variant | 4/4 | ENST00000399286.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE1 | ENST00000399286.3 | c.106C>T | p.Arg36Cys | missense_variant | 4/4 | 1 | NM_000219.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000496 AC: 4AN: 80572Hom.: 2 Cov.: 11
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251368Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135892
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000827 AC: 7AN: 845936Hom.: 3 Cov.: 23 AF XY: 0.00000238 AC XY: 1AN XY: 420738
GnomAD4 genome AF: 0.0000496 AC: 4AN: 80572Hom.: 2 Cov.: 11 AF XY: 0.00 AC XY: 0AN XY: 39312
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2024 | Observed 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 30, 2023 | 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. 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 submitter | clinical testing | Ambry Genetics | Mar 28, 2024 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at