rs746935735
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000070.3(CAPN3):c.402del(p.Ile135LeufsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CAPN3
NM_000070.3 frameshift
NM_000070.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
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 15-42386187-GC-G is Pathogenic according to our data. Variant chr15-42386187-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 286591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386187-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.402del | p.Ile135LeufsTer4 | frameshift_variant | 3/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.402del | p.Ile135LeufsTer4 | frameshift_variant | 3/23 | ||
CAPN3 | NM_173087.2 | c.402del | p.Ile135LeufsTer4 | frameshift_variant | 3/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.402del | p.Ile135LeufsTer4 | frameshift_variant | 3/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251414Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
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135874
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GnomAD4 exome Cov.: 31
GnomAD4 exome
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31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 11, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 286591). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 21204801). This variant is present in population databases (rs746935735, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ile135Leufs*4) 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). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 03, 2016 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at