rs1555420507
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000070.3(CAPN3):c.632+4A>G variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
CAPN3
NM_000070.3 splice_donor_region, intron
NM_000070.3 splice_donor_region, intron
Scores
1
1
Splicing: ADA: 0.9977
2
Clinical Significance
Conservation
PhyloP100: 6.24
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-42387890-A-G is Pathogenic according to our data. Variant chr15-42387890-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550589.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.632+4A>G | splice_donor_region_variant, intron_variant | ENST00000397163.8 | |||
CAPN3 | NM_024344.2 | c.632+4A>G | splice_donor_region_variant, intron_variant | ||||
CAPN3 | NM_173087.2 | c.632+4A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.632+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2022 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 4 skipping and introduces a premature termination codon (PMID: 18563459). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 550589). This variant is also known as IVS4+4A>G. This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18563459, 33335567). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2017 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 02, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at