rs141563497
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_001103.4(ACTN2):c.2551C>T(p.Arg851Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,160 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. R851H) 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 -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.2551C>T | p.Arg851Cys | missense_variant | 21/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.2551C>T | p.Arg851Cys | missense_variant | 21/21 | ||
ACTN2 | NR_184402.1 | n.2923C>T | non_coding_transcript_exon_variant | 23/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.2551C>T | p.Arg851Cys | missense_variant | 21/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251142Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135800
GnomAD4 exome AF: 0.0000992 AC: 145AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76AN XY: 727206
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74486
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, flagged submission | clinical testing | GeneDx | Dec 05, 2016 | The R851C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In addition, the R851C 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. Moreover, 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. Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, all of which would further clarify pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2022 | - - |
Dilated cardiomyopathy 1AA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1AA, with or without LVNC (MIM#612158), hypertrophic cardiomyopathy, 23, with or without LVNC (MIM#612158), congenital myopathy with structured cores and Z-line abnormalities (MIM#618654) and adult onset distal myopathy, 6 (MIM#618655) (PMID: 27287556). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - Variant is heterozygous. (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v2: 39 heterozygotes, 0 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg851His): 13 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ca2+ insensitive EF hand domain (PDB). It should also be noted that this variant is a methylated arginine site and that genetic changes at these sites has been suggested to be associated with cardiac disease (PMID: 27600370). (I) 0710 – Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg851His) variant has been classified as a VUS by clinical diagnostic laboratories and also reported once as a VUS in the literature (ClinVar; PMID: 23861362) (I). 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2022 | The p.R851C variant (also known as c.2551C>T), located in coding exon 21 of the ACTN2 gene, results from a C to T substitution at nucleotide position 2551. The arginine at codon 851 is replaced by cysteine, an amino acid with highly dissimilar properties. 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. - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at