1-236761070-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_001103.4(ACTN2):c.2423C>T(p.Thr808Ile) 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 1,614,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. T808S) has been classified as Likely benign.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.2423C>T | p.Thr808Ile | missense_variant | 20/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.2423C>T | p.Thr808Ile | missense_variant | 20/21 | ||
ACTN2 | NR_184402.1 | n.2795C>T | non_coding_transcript_exon_variant | 22/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.2423C>T | p.Thr808Ile | missense_variant | 20/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152174Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251494Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135920
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152174Hom.: 1 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74330
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 28, 2021 | Variant summary: ACTN2 c.2423C>T (p.Thr808Ile) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251494 control chromosomes, predominantly at a frequency of 0.00055 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2423C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 13, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#412276; Landrum et al., 2016) - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 30, 2016 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2022 | The p.T808I variant (also known as c.2423C>T), located in coding exon 20 of the ACTN2 gene, results from a C to T substitution at nucleotide position 2423. The threonine at codon 808 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 06, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at