rs34604640
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_005472.5(KCNE3):āc.116C>Gā(p.Pro39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39S) has been classified as Likely benign.
Frequency
Consequence
NM_005472.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE3 | NM_005472.5 | c.116C>G | p.Pro39Arg | missense_variant | 3/3 | ENST00000310128.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE3 | ENST00000310128.9 | c.116C>G | p.Pro39Arg | missense_variant | 3/3 | 1 | NM_005472.5 | P1 | |
ENST00000533008.1 | n.155-26729G>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251228Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135768
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461646Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49AN XY: 727084
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74494
ClinVar
Submissions by phenotype
Brugada syndrome 6 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 23, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2022 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 39 of the KCNE3 protein (p.Pro39Arg). This variant is present in population databases (rs34604640, gnomAD 0.02%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19306396). ClinVar contains an entry for this variant (Variation ID: 582464). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect KCNE3 function (PMID: 19306396). 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 | Sep 01, 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at