rs886042478
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong
The NM_000070.3(CAPN3):c.245C>T(p.Pro82Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,192 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P82P) has been classified as Likely benign.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.245C>T | p.Pro82Leu | missense_variant | 1/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.245C>T | p.Pro82Leu | missense_variant | 1/23 | ||
CAPN3 | NM_173087.2 | c.245C>T | p.Pro82Leu | missense_variant | 1/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.245C>T | p.Pro82Leu | missense_variant | 1/24 | 1 | NM_000070.3 | P2 | |
CAPN3 | ENST00000357568.8 | c.245C>T | p.Pro82Leu | missense_variant | 1/23 | 1 | |||
CAPN3 | ENST00000349748.8 | c.245C>T | p.Pro82Leu | missense_variant | 1/21 | 1 | |||
CAPN3 | ENST00000318023.11 | c.245C>T | p.Pro82Leu | missense_variant | 1/23 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249310Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134926
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727224
GnomAD4 genome AF: 0.0000459 AC: 7AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74484
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 04, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 11, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12461690, 12890817, 15689361, 16100770, 16141003, 15221789, 16372320, 15351423, 20635405, 14981715, 27023906, 17157502, 31980526, 31862442, 27447704, 26886200, 29970176, 35157181, 25135358, 31555977, 35894554, 36385624) - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 15, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the CAPN3 protein (p.Pro82Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 12461690, 12890817, 15221789, 15351423, 16100770, 16141003, 16372320, 17157502, 20635405, 25135358, 26886200, 27447704). ClinVar contains an entry for this variant (Variation ID: 282783). 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%. 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 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at