rs150226817
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6
The NM_000070.3(CAPN3):c.1543G>A(p.Gly515Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,094 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G515G) has been classified as Likely benign.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1543G>A | p.Gly515Arg | missense_variant | 13/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.1543G>A | p.Gly515Arg | missense_variant | 13/23 | ||
CAPN3 | NM_173087.2 | c.1399G>A | p.Gly467Arg | missense_variant | 12/21 | ||
CAPN3 | NM_173088.2 | c.7G>A | p.Gly3Arg | missense_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1543G>A | p.Gly515Arg | missense_variant | 13/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000309 AC: 47AN: 152150Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251386Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135876
GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461826Hom.: 1 Cov.: 33 AF XY: 0.0000935 AC XY: 68AN XY: 727216
GnomAD4 genome AF: 0.000322 AC: 49AN: 152268Hom.: 1 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 10, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2021 | 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: 33250842) - |
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2022 | Variant summary: CAPN3 c.1543G>A (p.Gly515Arg) results in a non-conservative amino acid change located in the subdomain III (IPR033883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 150922 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0011 including 1 homozygote (in the gnomAD database, v3.1 genomes dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no clear conclusions about variant significance. The variant, c.1543G>A, has been reported in the literature in an individual affected with proximal myopathy, who also carried a (likely) pathogenic CAPN3 variant, however the phase of these two variants was not determined (Chakravorty_2020). On the other hand, the variant was also reported in 3 individuals affected with limb-girdle muscular dystrophy (LGMD), however, two of these patients also carried two co-occurring pathogenic variants in other genes, which could explain the phenotype, while the 3rd patient carried a potentially pathogenic CAPN3 variant in cis (LOVD, PMID 30564623). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 515 of the CAPN3 protein (p.Gly515Arg). This variant is present in population databases (rs150226817, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 254861). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at