1-236762486-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_001103.4(ACTN2):c.2552G>A(p.Arg851His) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R851C) has been classified as Likely benign.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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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.2552G>A | p.Arg851His | missense_variant | 21/21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.2552G>A | p.Arg851His | missense_variant | 21/21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.2924G>A | non_coding_transcript_exon_variant | 23/23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251162Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135812
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461824Hom.: 1 Cov.: 31 AF XY: 0.0000550 AC XY: 40AN XY: 727208
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2022 | Identified in one patient from a DCM cohort, however, patient-specific clinical details were not provided (Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221) - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 07, 2015 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2023 | The p.R851H variant (also known as c.2552G>A), located in coding exon 21 of the ACTN2 gene, results from a G to A substitution at nucleotide position 2552. The arginine at codon 851 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort, and has been detected in a dilated cardiomyopathy cohort; however, details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Mazzarotto F et al. Circulation. 2020 Feb;141(5):387-398). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 | Sep 05, 2023 | Variant summary: ACTN2 c.2552G>A (p.Arg851His) results in a non-conservative amino acid change located in the EF-hand, Ca insensitive domain (IPR014837) of 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 4.8e-05 in 251162 control chromosomes. The observed variant frequency is approximately 2 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.2552G>A has been reported in the literature in at least one individual affected with Cardiomyopathy without strong evidence for causality (e.g. Mazzarotto_2020). 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. The following publication have been ascertained in the context of this evaluation (PMID: 31983221). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 15, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at