rs559395092
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_001103.4(ACTN2):c.1180C>T(p.Arg394Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R394Q) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1180C>T | p.Arg394Trp | missense_variant | 11/21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.1180C>T | p.Arg394Trp | missense_variant | 11/21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.1552C>T | non_coding_transcript_exon_variant | 13/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1180C>T | p.Arg394Trp | missense_variant | 11/21 | 1 | NM_001103.4 | ENSP00000355537.4 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251468Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135914
GnomAD4 exome AF: 0.0000793 AC: 116AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64AN XY: 727246
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74410
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2017 | A variant of uncertain significance has been identified in the ACTN2 gene. The R394W variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 2/16512 (0.012%) alleles from individuals of South Asian ancestry, and in 3/66728 (0.004%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R394W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 19, 2018 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 28, 2018 | - - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 07, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at