rs148355179
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_000890.5(KCNJ5):c.439G>A(p.Glu147Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000890.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ5 | NM_000890.5 | c.439G>A | p.Glu147Lys | missense_variant | 2/3 | ENST00000529694.6 | NP_000881.3 | |
KCNJ5 | NM_001354169.2 | c.439G>A | p.Glu147Lys | missense_variant | 3/4 | NP_001341098.1 | ||
KCNJ5 | XM_011542810.4 | c.439G>A | p.Glu147Lys | missense_variant | 2/3 | XP_011541112.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNJ5 | ENST00000529694.6 | c.439G>A | p.Glu147Lys | missense_variant | 2/3 | 1 | NM_000890.5 | ENSP00000433295.1 | ||
KCNJ5 | ENST00000338350.4 | c.439G>A | p.Glu147Lys | missense_variant | 3/4 | 1 | ENSP00000339960.4 | |||
KCNJ5 | ENST00000533599.1 | c.439G>A | p.Glu147Lys | missense_variant | 1/2 | 1 | ENSP00000434266.1 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251494Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135922
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461886Hom.: 0 Cov.: 59 AF XY: 0.0000605 AC XY: 44AN XY: 727244
GnomAD4 genome AF: 0.000118 AC: 18AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74328
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2022 | Variant summary: KCNJ5 c.439G>A (p.Glu147Lys) results in a conservative amino acid change located in the Potassium channel, inwardly rectifying, transmembrane domain (IPR040445) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency does not allow firm conclusions about variant significance. To our knowledge, no occurrence of c.439G>A in individuals affected with Hyperaldosteronism, Familial, Type III/Long QT syndrome 13 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Long QT syndrome 13;C3838758:Familial hyperaldosteronism type III Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 14, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 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 - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the KCNJ5 protein (p.Glu147Lys). This variant is present in population databases (rs148355179, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with KCNJ5-related conditions. ClinVar contains an entry for this variant (Variation ID: 432222). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ5 protein function with a positive predictive value of 80%. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2024 | The p.E147K variant (also known as c.439G>A), located in coding exon 1 of the KCNJ5 gene, results from a G to A substitution at nucleotide position 439. The glutamic acid at codon 147 is replaced by lysine, an amino acid with similar properties, and is located in the intramembrane, helical pore-forming domain. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at