rs74315447
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_172201.2(KCNE2):āc.161T>Cā(p.Met54Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M54V) has been classified as Uncertain significance.
Frequency
Consequence
NM_172201.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE2 | NM_172201.2 | c.161T>C | p.Met54Thr | missense_variant | 2/2 | ENST00000290310.4 | |
LOC105372791 | XR_937683.3 | n.1215A>G | non_coding_transcript_exon_variant | 2/2 | |||
LOC105372791 | XR_007067848.1 | n.1250A>G | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE2 | ENST00000290310.4 | c.161T>C | p.Met54Thr | missense_variant | 2/2 | 1 | NM_172201.2 | P1 | |
ENST00000440403.2 | n.650A>G | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000262 AC: 66AN: 251474Hom.: 0 AF XY: 0.000191 AC XY: 26AN XY: 135910
GnomAD4 exome AF: 0.000140 AC: 204AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 100AN XY: 727248
GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74368
ClinVar
Submissions by phenotype
Long QT syndrome 6 Pathogenic:1Uncertain:1Other:1
risk factor, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Mar 17, 2018 | This c.161T>C (p.Met54Thr) variant in the KCNE2 gene has been reported in patients with variable presentations such as arrythmias, sinus bradycardia and long QT syndrome [PMID 10219239, 19716085, 23631727]. This variant was first reported in a patient with atypical response to exercise with prolonged QTc intervals [PMID 10219239]. In vitro functional assays showed that the variant affect protein function [PMID 23631727, 20042375, 24569893]. This variant has been detected in 29 heterozygous individuals from Europe in the ExAC population database (http://exac.broadinstitute.org/variant/21-35742938-T-C). Methionine at amino acid position 54 of the KCNE2 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Met54Thr change to be deleterious. This variant is thus classified as a risk factor. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 16, 1999 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the KCNE2 protein (p.Met54Thr). This variant is present in population databases (rs74315447, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KCNE2-related conditions (PMID: 10219239, 23936059, 26159999, 31737537, 33626434). ClinVar contains an entry for this variant (Variation ID: 6053). 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 disruptive. Experimental studies have shown that this missense change affects KCNE2 function (PMID: 19219384, 20042375, 23631727, 31235733). 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. - |
KCNE2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The KCNE2 c.161T>C (p.Met54Thr) variant has been reported in at least four studies in individuals with long QT syndrome (LQTS), drug-induced LQTS, or sudden unexplained death (SUD), and is found in a heterozygous state in six individuals (Abbot et al. 1999; Sesti et al. 2000; Kapplinger et al. 2009; Wang et al. 2014). The p.Met54Thr variant was also identified in two of over 6100 presumed healthy individuals (Freudenberg-Hua et al. 2014; Ghouse et al. 2015). The p.Met54Thr variant was absent from over 2300 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies indicated that the p.Met54Thr variant causes a reduction in current density in the potassium ion channel (Abbot et al. 1999; Sesti et al. 2000; Wu et al. 2010). Based on the collective evidence, the p.Met54Thr variant is classified as likely pathogenic for KCNE2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Multiple functional studies demonstrate that M54T has a significant effect on potassium ion channel function in the heart (Abbott et al., 1999; Lu et al., 2003; McCrossan et al., 2009; Wu et al., 2010); This variant is associated with the following publications: (PMID: 20042375, 31447099, 31737537, 24569893, 24631769, 25333069, 10984545, 24631775, 26159999, 12923204, 19716085, 22677073, 23631727, 26859003, 28316956, 28794082, 10219239, 22378279, 25637381, 18006462, 14760488, 29661707, 30123799, 34426522, 19219384, 32078429, 33626434, 34930020, 31980526, 34709746, 33324689, 34247280, 23936059, 35125083, 31235733) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2020 | 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. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:19716085;PMID:20042375;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at