chr1-236751635-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_001103.4(ACTN2):c.1822C>T(p.Arg608Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,748 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. R608Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1822C>T | p.Arg608Trp | missense_variant | 15/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.1822C>T | p.Arg608Trp | missense_variant | 15/21 | ||
ACTN2 | NR_184402.1 | n.2194C>T | non_coding_transcript_exon_variant | 17/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1822C>T | p.Arg608Trp | missense_variant | 15/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251230Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135784
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461652Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727138
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74294
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 30, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 02, 2012 | The Arg608Trp variant in ACTN2 has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) predict an impact t o the protein but their accuracy is unknown. Additional information is needed to fully assess the clinical significance of this variant. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2020 | The c.1822C>T (p.R608W) alteration is located in exon 15 (coding exon 15) of the ACTN2 gene. This alteration results from a C to T substitution at nucleotide position 1822, causing the arginine (R) at amino acid position 608 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, 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 | Nov 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at