rs370591031
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002234.4(KCNA5):c.1327A>G(p.Ile443Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I443M) has been classified as Uncertain significance.
Frequency
Consequence
NM_002234.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNA5 | NM_002234.4 | c.1327A>G | p.Ile443Val | missense_variant | 1/1 | ENST00000252321.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNA5 | ENST00000252321.5 | c.1327A>G | p.Ile443Val | missense_variant | 1/1 | NM_002234.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251428Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135904
GnomAD4 exome AF: 0.000137 AC: 200AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.000132 AC XY: 96AN XY: 727242
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74312
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 7 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 15, 2021 | The KCNA5 c.1327A>G; p.Ile443Val variant (rs370591031) is reported in the literature in an individual diagnosed with pulmonary arterial hypertension (Zhu 2019), and is also reported in ClinVar (Variation ID: 469583). This variant is found in the general population with an overall allele frequency of 0.006% (18/282786 alleles) in the Genome Aggregation Database. The isoleucine at codon 443 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.674). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Zhu et al. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. Genome Med. 2019 Nov 14;11(1):69. PMID: 31727138. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 30, 2023 | 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. 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 not expected to disrupt KCNA5 protein function. ClinVar contains an entry for this variant (Variation ID: 469583). This missense change has been observed in individual(s) with pulmonary arterial hypertension (PMID: 31727138). This variant is present in population databases (rs370591031, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 443 of the KCNA5 protein (p.Ile443Val). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 03, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2021 | Reported in a patient with idiopathic pulmonary hypertension (Zhu et al., 2019); however, additional clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 469583; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31727138) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at