12-5044188-T-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_002234.4(KCNA5):c.41T>G(p.Met14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,537,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNA5 | NM_002234.4 | c.41T>G | p.Met14Arg | missense_variant | 1/1 | ENST00000252321.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNA5 | ENST00000252321.5 | c.41T>G | p.Met14Arg | missense_variant | 1/1 | NM_002234.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152100Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000149 AC: 2AN: 134152Hom.: 0 AF XY: 0.0000136 AC XY: 1AN XY: 73278
GnomAD4 exome AF: 0.00000794 AC: 11AN: 1385002Hom.: 0 Cov.: 31 AF XY: 0.00000731 AC XY: 5AN XY: 683604
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74418
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 7 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 12, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with KCNA5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.04%). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 14 of the KCNA5 protein (p.Met14Arg). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2022 | The c.41T>G (p.M14R) alteration is located in exon 1 (coding exon 1) of the KCNA5 gene. This alteration results from a T to G substitution at nucleotide position 41, causing the methionine (M) at amino acid position 14 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at