rs74315448
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_172201.2(KCNE2):c.170T>C(p.Ile57Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000655 in 1,614,210 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 5 hom. )
Consequence
KCNE2
NM_172201.2 missense
NM_172201.2 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 6.81
Genes affected
KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.32147172).
BP6
Variant 21-34370648-T-C is Benign according to our data. Variant chr21-34370648-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6054.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=1, Uncertain_significance=3}. Variant chr21-34370648-T-C is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 106 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KCNE2 | NM_172201.2 | c.170T>C | p.Ile57Thr | missense_variant | 2/2 | ENST00000290310.4 | NP_751951.1 | |
| LOC105372791 | XR_937683.3 | n.1206A>G | non_coding_transcript_exon_variant | 2/2 | ||||
| LOC105372791 | XR_007067848.1 | n.1241A>G | non_coding_transcript_exon_variant | 2/2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNE2 | ENST00000290310.4 | c.170T>C | p.Ile57Thr | missense_variant | 2/2 | 1 | NM_172201.2 | ENSP00000290310 | P1 | |
| ENST00000440403.2 | n.641A>G | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes 0.000703 AC: 107AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00105 AC: 265AN: 251484Hom.: 3 AF XY: 0.00118 AC XY: 160AN XY: 135918
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GnomAD4 exome AF: 0.000651 AC: 951AN: 1461890Hom.: 5 Cov.: 31 AF XY: 0.000719 AC XY: 523AN XY: 727248
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GnomAD4 genome 0.000696 AC: 106AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5Benign:11Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Long QT syndrome 6 Pathogenic:1Uncertain:4Benign:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 16, 1999 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Nov 27, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 24, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Jun 25, 2019 | - - |
not provided Benign:5Other:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2017 | Variant summary: The KCNE2 c.170T>C (p.Ile57Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense change of Ile57 which is located in a predicted transmembrane domain. 5/5 in silico tools predict a damaging outcome for this variant, and functional studies indicate that this variant compromises function: 1) I57T-hMiRP1 diminished potassium flux through MiRP1/HERG channel complexes (Abbott_Cell_1999), 2) KCNE2-I57T decreased the rate of activation of the KCNQ1 current, abolished the hump of the tail currents upon repolarization, accelerated the deactivation process (127ms vs 552ms for WT), and shifted the voltage dependency of the channel activation towards more depolarized potentials (Tinel_EMBO_200), and 3) KCNQ2+KCNE2-I57T had a significantly increased (227ms vs 156ms for WT) time constant of deactivation (no significant change in time constant of activation), while KCNQ2+KCNQ3+KCNE2-I57T significantly decreased (68.0ms vs 99.5ms for WT) the time constant of activation (no significant change in time constant of deactivation; Tinel_FEBS_2000). However the variant 1) did not reduce mean current density of hMiRP1-Kv2.1 channels, 2) had no significant effect on V1/2 activation (McCrossan_J Membr Biol_2009), and 3) had the same sensitivity to oxatomide as wild type, thus the variant did not alter sensitivity to drug inhibition (Sesti_PNAS_2000). Furthermore, it has not been established if these quantitative and qualitative functional observations are sufficient to induce arrhythmia in the absence of other precipitating factors; therefore, this variant may only be a risk allele. This variant was found in 107/125050 control chromosomes (including one homozygote) including ExAC at a frequency of 0.0008557, which is approximately 128 times the estimated maximal expected allele frequency of a pathogenic KCNE2 variant (0.0000067), suggesting this variant is likely a benign polymorphism.This variant has been reported in many patients with LQTS and two reports of patients with drug induced LQTS, but majority of reports in the literature do not provide co-segregation data. This variant was found to in one neonate with mild LQTS and his two relatives (including mother) in one family, however clinical data was only provided for the proband that had a QT interval of 462ms as a newborn, but had normal QTc at follow-up (Schwartz_Circ_2009). The variant was reported in a patient with LQTS and neonatal seizures who also carried another pathogenic variant SCN5A R1623Q and the unaffected father, brother, and sister did not carry this KCNE2 c.170T>C variant, suggesting that this variant was not causative in this family (Heron_Epilepsia_2010). In another family with 5 affected WolffParkinsonWhite (WPW) syndrome, this variant was found in only 2 affected and also in 4 unaffected family members; a pathogenic MYH6 variant was found to co-segregate with disease in this family as well, thus suggesting that KCNE2 c.170T>C was not causative in this family (Bowels_AJMG_2015). In addition, two patients with primary electrical disease also carried another VUS, ANK2 p.His931Gln and CACNB2 p.Ala340Thr, respectively (Proost_2017). The variant is reported with conflicting classifications from multiple clinical diagnostic laboratories or databases, with the most recent reports being VUS and likely benign (2016). Recently, this variant was observed in six homozygotes who did not express phenotype from Saudi Human Genome Program (Abouelhoda_GenomeBiology_2016). Taken together, this the variant was classified as likely benign. - |
| not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:16922724;PMID:19716085;PMID:20042375;PMID:22378279). - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2020 | This variant is associated with the following publications: (PMID: 22378279, 10219239, 24796621, 24144883, 24055113, 25637381, 19841298, 20042375, 16922724, 19716085, 23382499, 10984545, 25696450, 19863579, 26159999, 24606995, 23098067, 19862833, 11101505, 11034315, 28341588, 27595200, 27884173, 29672598, 29032884, 28794082, 30986657, 31019283, 31320904, 31737537, 30847666) - |
Cardiac arrhythmia Uncertain:1Benign:1
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
KCNE2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 24, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 10, 2018 | 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. - |
Atrial fibrillation, familial, 4 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
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