11-74457425-G-A
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005472.5(KCNE3):c.139C>T(p.Arg47Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47Q) has been classified as Likely benign.
Frequency
Consequence
NM_005472.5 missense
Scores
Clinical Significance
Conservation
Publications
- Brugada syndrome 6Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
- Brugada syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152214Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251136 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461492Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726984 show subpopulations
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352 show subpopulations
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
The p.R47W variant (also known as c.139C>T), located in coding exon 1 of the KCNE3 gene, results from a C to T substitution at nucleotide position 139. The arginine at codon 47 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Brugada syndrome 6 Uncertain:1
This variant has not been reported in the literature in individuals affected with KCNE3-related conditions. 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 1771723). This variant is present in population databases (rs17215444, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 47 of the KCNE3 protein (p.Arg47Trp). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at