rs1555421871
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000070.3(CAPN3):c.1322del(p.Gly441ValfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000343 in 1,458,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CAPN3
NM_000070.3 frameshift
NM_000070.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.90
Genes affected
CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-42399616-CG-C is Pathogenic according to our data. Variant chr15-42399616-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 281062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399616-CG-C is described in Lovd as [Pathogenic]. Variant chr15-42399616-CG-C is described in Lovd as [Pathogenic]. Variant chr15-42399616-CG-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1322del | p.Gly441ValfsTer22 | frameshift_variant | 10/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.1322del | p.Gly441ValfsTer22 | frameshift_variant | 10/23 | ||
CAPN3 | NM_173087.2 | c.1178del | p.Gly393ValfsTer22 | frameshift_variant | 9/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1322del | p.Gly441ValfsTer22 | frameshift_variant | 10/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
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GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247520Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133934
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458896Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725306
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GnomAD4 genome ? Cov.: 31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | This sequence change creates a premature translational stop signal (p.Gly441Valfs*22) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 281062). This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 15733273). This variant is present in population databases (no rsID available, gnomAD 0.0009%). - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 12, 2017 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
Cardiac arrhythmia;C0026850:Muscular dystrophy;C0151786:Muscle weakness;C0409338:Elbow flexion contracture;C1859523:Lower-limb joint contracture Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 24, 2014 | - - |
CAPN3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.1322delG;p.(Gly441Valfs*22) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 26501342; PMID: 25135358; PMID: 17702496; PMID: 17236769) - PS4. This variant is not present in population databases (rs1555421871- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Gly441Valfs*22) was detected in trans with a pathogenic variant (PMID: 26501342; PMID: 25135358) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 09, 2015 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at