rs563171274
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The NM_001103.4(ACTN2):c.1312C>T(p.Arg438Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,228 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R438Q) has been classified as Likely benign.
Frequency
Consequence
NM_001103.4 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 | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1312C>T | p.Arg438Trp | missense_variant | 12/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.1312C>T | p.Arg438Trp | missense_variant | 12/21 | ||
ACTN2 | NR_184402.1 | n.1684C>T | non_coding_transcript_exon_variant | 14/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1312C>T | p.Arg438Trp | missense_variant | 12/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251272Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135838
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727244
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152350Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2023 | The p.R438W variant (also known as c.1312C>T), located in coding exon 12 of the ACTN2 gene, results from a C to T substitution at nucleotide position 1312. The arginine at codon 438 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is 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. - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at