rs1555423027
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_000070.3(CAPN3):c.2050+1del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,164,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CAPN3
NM_000070.3 splice_donor
NM_000070.3 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
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 20 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 28, new splice context is: gggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-42409844-CG-C is Pathogenic according to our data. Variant chr15-42409844-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42409844-CG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.2050+1del | splice_donor_variant | ENST00000397163.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.2050+1del | splice_donor_variant | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
GnomAD4 exome AF: 0.00000344 AC: 4AN: 1164392Hom.: 0 Cov.: 37 AF XY: 0.00000516 AC XY: 3AN XY: 581910
GnomAD4 exome
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37
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3
AN XY:
581910
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GnomAD4 genome ? Cov.: 29
GnomAD4 genome
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Cov.:
29
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 | Apr 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2023 | This sequence change affects a splice site in intron 18 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 557598). Disruption of this splice site has been observed in individuals with limb girdle muscular dystrophy (PMID: 11525884, 15689361, 26632398, 30107846). This variant is not present in population databases (gnomAD no frequency). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2022 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -25
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at