rs762471207
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000070.3(CAPN3):βc.1981delβ(p.Ile661Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.000038 ( 0 hom. )
Consequence
CAPN3
NM_000070.3 frameshift
NM_000070.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.86
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 15-42409368-GA-G is Pathogenic according to our data. Variant chr15-42409368-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 194691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42409368-GA-G is described in Lovd as [Pathogenic]. Variant chr15-42409368-GA-G is described in Lovd as [Pathogenic]. Variant chr15-42409368-GA-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1981del | p.Ile661Ter | frameshift_variant | 17/24 | ENST00000397163.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1981del | p.Ile661Ter | frameshift_variant | 17/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251340Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135832
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GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727208
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 04, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Ile661*) 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). This variant is present in population databases (rs762471207, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 25135358). ClinVar contains an entry for this variant (Variation ID: 194691). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 28, 2012 | - - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 05, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 25, 2019 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 09, 2024 | - - |
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