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rs74315448

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I57M) has been classified as Uncertain significance.

Frequency

Genomes: đť‘“ 0.00070 ( 0 hom., cov: 32)
Exomes đť‘“: 0.00065 ( 5 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

5
10
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:11O:1

Conservation

PhyloP100: 6.81
Variant links:
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: {not_provided=1, Likely_benign=8, Uncertain_significance=3}. Variant chr21-34370648-T-C is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd at 107 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNE2NM_172201.2 linkuse as main transcriptc.170T>C p.Ile57Thr missense_variant 2/2 ENST00000290310.4
LOC105372791XR_937683.3 linkuse as main transcriptn.1206A>G non_coding_transcript_exon_variant 2/2
LOC105372791XR_007067848.1 linkuse as main transcriptn.1241A>G non_coding_transcript_exon_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNE2ENST00000290310.4 linkuse as main transcriptc.170T>C p.Ile57Thr missense_variant 2/21 NM_172201.2 P1
ENST00000440403.2 linkuse as main transcriptn.641A>G non_coding_transcript_exon_variant 2/33

Frequencies

GnomAD3 genomes
AF:
0.000703
AC:
107
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00268
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.000500
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00105
AC:
265
AN:
251484
Hom.:
3
AF XY:
0.00118
AC XY:
160
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00188
Gnomad ASJ exome
AF:
0.00119
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000947
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00117
Gnomad OTH exome
AF:
0.00342
GnomAD4 exome
AF:
0.000651
AC:
951
AN:
1461890
Hom.:
5
Cov.:
31
AF XY:
0.000719
AC XY:
523
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000747
Gnomad4 AMR exome
AF:
0.00188
Gnomad4 ASJ exome
AF:
0.00119
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00109
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000480
Gnomad4 OTH exome
AF:
0.00161
GnomAD4 genome
AF:
0.000696
AC:
106
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.000631
AC XY:
47
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.00268
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000500
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.000993
Hom.:
1
Bravo
AF:
0.00102
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000881
AC:
107
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00174
EpiControl
AF:
0.00136

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 providedliterature onlyOMIMApr 16, 1999- -
Uncertain significance, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic HealthcareJun 25, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 24, 2019This 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 submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesNov 27, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneNov 21, 2018- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Likely benign, criteria provided, single submitterclinical testingInvitaeDec 30, 2023- -
not provided Benign:5Other:1
not provided, no classification providedliterature onlyCardiovascular 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, criteria provided, single submitterclinical testingGeneDxNov 18, 2020This 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) -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 01, 2017Variant 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. -
Cardiac arrhythmia Uncertain:1Benign:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
KCNE2-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 24, 2022This 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 submitterclinical testingAmbry GeneticsDec 10, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.40
Cadd
Pathogenic
26
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.32
T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
A
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.4
D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0080
D
Polyphen
1.0
D
Vest4
0.97
MVP
0.96
MPC
0.57
ClinPred
0.041
T
GERP RS
5.7
Varity_R
0.56
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs74315448; hg19: chr21-35742947; COSMIC: COSV51710065; COSMIC: COSV51710065; API