chr15-42410646-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000070.3(CAPN3):c.2243G>A(p.Arg748Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (β β ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R748G) has been classified as Pathogenic.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.2243G>A | p.Arg748Gln | missense_variant | 21/24 | ENST00000397163.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.2243G>A | p.Arg748Gln | missense_variant | 21/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152022Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251118Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135726
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461712Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727148
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152022Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74246
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:9
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 07, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | This c.2243G>A (p.Arg748Gln) missense variant in CAPN3 gene has been reported in the homozygous or compound heterozygous state in many individuals affected with limb girdle muscular dystrophy (LGMD) (Fanin et al., 2009; Fadaee et al., 2016; SΓ‘enz et al., 2005), and in one affected family it was shown to cosegregate with LGMD (Richard et al., 1997). Experimental studies have shown that this missense substitution reduces CAPN3 catalytic activity as measured by cleavage of an exogenous peptide, which was attributed to an increased rate of autoproteolytic degradation (Garnham et al., 2009). This variant is reported with the allele frequency (0.0051%) in the gnomAD and novel in 1000 genome database. This variant has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Arg at position 748 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg748Gln in CAPN3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 19, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 748 of the CAPN3 protein (p.Arg748Gln). This variant is present in population databases (rs587780290, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 9762961, 9777948, 10330340, 12461690, 15689361, 18563459, 18854869, 19015733, 22443334, 26404900, 27020652, 30028523). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128570). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Arg748Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD) This variant has been identified in 0.01455% (5/34372) of Latino chromosomes and 0.004166% (1/24006) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587780290). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. One study that examined a rat model with an analagous protein suggested that this variant affects protein catalytic activity (PMID: 19226146). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enought to determine pathogenicity. The p.Arg748Gln variant in CAPN3 has been reported in many individuals with LGMD in the homozygous and compound heterozygous states in ClinVar and the literature (Variation ID: 128570). This variant segregated with disease in 2 affected relatives from 1 family (PMID: 9150160). There are many reports of individuals with LGMD and this variant (in either the homozygous or compound heterozygous state) in ClinVar and the literature. Animal models in rats have shown that this variant causes LGMD via a deleterious effect on calpain protein catalytic activity (PMID: 19226146). In summary, the p.Arg748Gln variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PP3, PS3, PP1, PM3_Strong (Richards 2015). - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2017 | The R748Q variant in the CAPN3 gene has been reported previously in association with limb-girdle muscular dystrophy, type 2A. The affected individuals had onset within the first two decades of life, ranging from 2.5 years to 15 years of age and all had elevated creatine phosphokinase levels (Richards et al., 1997; Fattahi et al., 2017). The R748Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R748Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies in rat calpain 2 showed that R748Q, using the alternate nomenclature R628Q, reduced initial enzyme activity and catalytic activity, suggesting R748Q in human CAPN3 is damaging (Garnham et al., 2009). We interpret R748Q as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 10, 2017 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 30, 2023 | - - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at