chr1-236757492-C-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2
The NM_001103.4(ACTN2):c.2161C>A(p.Arg721Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R721H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.2161C>A | p.Arg721Ser | missense_variant | Exon 18 of 21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.2161C>A | p.Arg721Ser | missense_variant | Exon 18 of 21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.2533C>A | non_coding_transcript_exon_variant | Exon 20 of 23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000521 AC: 131AN: 251484Hom.: 0 AF XY: 0.000478 AC XY: 65AN XY: 135914
GnomAD4 exome AF: 0.000222 AC: 325AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 160AN XY: 727222
GnomAD4 genome AF: 0.000250 AC: 38AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74320
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
The p.Arg721Ser variant in ACTN2 has been identified by our laboratory in 1 adul t with DCM and 4 adults with HCM. This variant has also been identified in 39/66 732 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs149433837). Computational prediction tools and conse rvation analysis suggest that the p.Arg721Ser variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Arg721Ser variant is uncertain. -
Variant summary: ACTN2 c.2161C>A (p.Arg721Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251484 control chromosomes (gnomAD). The observed variant frequency is approximately 20.8- fold 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.2161C>A has been reported in the literature in at least one individual affected with Cardiomyopathy (Pugh_2014). This report does 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as likely benign (n=2) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:2
This variant is associated with the following publications: (PMID: 23861362, 24503780) -
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Hypertrophic cardiomyopathy 1 Uncertain:1
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Cardiomyopathy Benign:1
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ACTN2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
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Dilated cardiomyopathy 1AA Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at