rs376107921
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The NM_000070.3(CAPN3):c.1319G>A(p.Arg440Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,611,116 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1319G>A | p.Arg440Gln | missense_variant | 10/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.1319G>A | p.Arg440Gln | missense_variant | 10/23 | ||
CAPN3 | NM_173087.2 | c.1175G>A | p.Arg392Gln | missense_variant | 9/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1319G>A | p.Arg440Gln | missense_variant | 10/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152196Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000646 AC: 16AN: 247616Hom.: 0 AF XY: 0.000105 AC XY: 14AN XY: 133908
GnomAD4 exome AF: 0.000147 AC: 214AN: 1458920Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111AN XY: 725320
GnomAD4 genome AF: 0.000164 AC: 25AN: 152196Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2023 | 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: 15221789, 18334579, 20694146, 18055493, 15689361, 17236769, 31589614, 21984748, 17994539, 15725583, 30564623, 32906206, 24077912, 32528171, 18854869, 33250842, 19048948, 25326637, 17526799, 33337384, 35169782) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 26, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Experiments in patient-derived samples showed absence or significant reduction in CAPN3 protein level/activity in multiple patients (PMID: 15221789, 17994539, 18055493). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 28, 2020 | PS4, PM2, PM3, PM5, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 27, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 25, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 10, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the CAPN3 protein (p.Arg440Gln). This variant is present in population databases (rs376107921, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 15221789, 18055493, 19048948, 20694146, 21984748, 25326637). ClinVar contains an entry for this variant (Variation ID: 217147). 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: 15221789, 18055493, 19048948, 20694146). For these reasons, this variant has been classified as Pathogenic. - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 20, 2021 | - - |
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