chr1-236739531-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2
The NM_001103.4(ACTN2):c.1106C>T(p.Ser369Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S369S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1106C>T | p.Ser369Leu | missense_variant, splice_region_variant | 10/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.1106C>T | p.Ser369Leu | missense_variant, splice_region_variant | 10/21 | ||
ACTN2 | NR_184402.1 | n.1478C>T | splice_region_variant, non_coding_transcript_exon_variant | 12/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1106C>T | p.Ser369Leu | missense_variant, splice_region_variant | 10/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152252Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250048Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135302
GnomAD4 exome AF: 0.0000944 AC: 138AN: 1461634Hom.: 0 Cov.: 67 AF XY: 0.0000866 AC XY: 63AN XY: 727112
GnomAD4 genome AF: 0.000184 AC: 28AN: 152252Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16AN XY: 74376
ClinVar
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 369 of the ACTN2 protein (p.Ser369Leu). This variant is present in population databases (rs747400815, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ACTN2-related conditions (PMID: 30086531). ClinVar contains an entry for this variant (Variation ID: 296505). 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. - |
Dilated cardiomyopathy 1AA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2023 | The p.S369L variant (also known as c.1106C>T), located in coding exon 10 of the ACTN2 gene, results from a C to T substitution at nucleotide position 1106. The serine at codon 369 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in a sudden infant death case with additional cardiac variants and limited clinical details (Campuzano O et al. Forensic Sci Int Genet, 2018 11;37:54-63). 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 12, 2023 | Variant summary: ACTN2 c.1106C>T (p.Ser369Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250048 control chromosomes. The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1106C>T has been reported in the literature in individuals affected with alcoholic cardiomyopathy or sudden cardiac death without strong evidence of causality (Ware_2018, Campuzano_2018). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29773157, 30086531). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence, and classified it as uncertain significance (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at