rs780431842
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_001103.4(ACTN2):c.1906G>A(p.Glu636Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E636G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1906G>A | p.Glu636Lys | missense_variant | Exon 16 of 21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.1906G>A | p.Glu636Lys | missense_variant | Exon 16 of 21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.2278G>A | non_coding_transcript_exon_variant | Exon 18 of 23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251238Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135842
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461808Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11AN XY: 727204
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 636 of the ACTN2 protein (p.Glu636Lys). This variant is present in population databases (rs780431842, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 222484). 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 disruptive. 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. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.E636K variant (also known as c.1906G>A), located in coding exon 16 of the ACTN2 gene, results from a G to A substitution at nucleotide position 1906. The glutamic acid at codon 636 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at