rs1555420647
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000070.3(CAPN3):c.741_751del(p.Met248HisfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
CAPN3
NM_000070.3 frameshift
NM_000070.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.23
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 15-42389033-TGACATGTACAA-T is Pathogenic according to our data. Variant chr15-42389033-TGACATGTACAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.741_751del | p.Met248HisfsTer16 | frameshift_variant | 5/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.741_751del | p.Met248HisfsTer16 | frameshift_variant | 5/23 | ||
CAPN3 | NM_173087.2 | c.741_751del | p.Met248HisfsTer16 | frameshift_variant | 5/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.741_751del | p.Met248HisfsTer16 | frameshift_variant | 5/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 21, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant has not been reported in the literature in individuals with CAPN3-related disease. This sequence change creates a premature translational stop signal (p.Met248Hisfs*16) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 27, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at