rs547194943
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005472.5(KCNE3):c.20C>T(p.Thr7Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 1 hom. )
Consequence
KCNE3
NM_005472.5 missense
NM_005472.5 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 4.83
Genes affected
KCNE3 (HGNC:6243): (potassium voltage-gated channel subfamily E regulatory subunit 3) 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 type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the kidney. A missense mutation in this gene is associated with hypokalemic periodic paralysis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.062900394).
BP6
Variant 11-74457544-G-A is Benign according to our data. Variant chr11-74457544-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNE3 | NM_005472.5 | c.20C>T | p.Thr7Met | missense_variant | 3/3 | ENST00000310128.9 | NP_005463.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNE3 | ENST00000310128.9 | c.20C>T | p.Thr7Met | missense_variant | 3/3 | 1 | NM_005472.5 | ENSP00000310557.4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251368Hom.: 1 AF XY: 0.0000368 AC XY: 5AN XY: 135844
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461844Hom.: 1 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727224
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Dec 02, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNE3 p.Thr7Met Given the weak gene-phenotype data, the lack of case data, and the presence at low frequencies in unselected samples (reviewed below) we consider this variant a variant of uncertain significance. The KCNE3 gene has been associated with Brugada syndrome type 6 (Deplon et al 2008) and periodic paralysis (Abbott et al 2001). Antzelevitch's group used a candidate gene approach to study KCNE3 in 105 Brugada probands and found p.Arg99His in one proband. It was also presented in 3 other affected family members. That variant has since been reported online in 10 of 58,613 individuals in the Exome Aggregation Consortium dataset. Subsequently, anther group sequenced SCN5A, SCN1B, SCN3B, CACNA1C, CACNB2, KCNE3 and KCNE5 in 40 patients with Brugada syndrome and found p.Thr4Ala in one Japanese patient (Nakajima et al 2012). That variant is present in 9 of 4379 east Asian individuals in ExAC. The variant is novel. This is is a non-conservative amino acid substitution. However, this substitution occurs at a position that is not conserved across species. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function. The variant was reported online in 8 of 61,385 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 1st, 2014). The highest frequency was in 4 of 4379 East Asian individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) - |
Brugada syndrome 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 7 of the KCNE3 protein (p.Thr7Met). This variant is present in population databases (rs547194943, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with KCNE3-related conditions. ClinVar contains an entry for this variant (Variation ID: 190800). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;T;T;T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;D;D;D
REVEL
Benign
Sift
Benign
T;T;T;D;D;.
Sift4G
Benign
T;T;.;.;.;.
Polyphen
B;B;.;.;.;.
Vest4
MutPred
Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);
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