chr15-42409845-G-A
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_000070.3(CAPN3):c.2050+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000070.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.2050+1G>A | splice_donor_variant | ENST00000397163.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.2050+1G>A | splice_donor_variant | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000725 AC: 1AN: 137946Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251028Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135740
GnomAD4 exome AF: 0.00000393 AC: 5AN: 1272654Hom.: 0 Cov.: 37 AF XY: 0.00000314 AC XY: 2AN XY: 636152
GnomAD4 genome ? AF: 0.00000725 AC: 1AN: 137946Hom.: 0 Cov.: 29 AF XY: 0.0000151 AC XY: 1AN XY: 66056
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | 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: 553754). Disruption of this splice site has been observed in individuals with limb-girdle muscular dystrophy (PMID: 11525884, 26632398, 26677118). This variant is present in population databases (rs768374736, gnomAD 0.01%). This sequence change affects a donor 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 10, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 22, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 18, 2024 | Variant summary: CAPN3 c.2050+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251028 control chromosomes. c.2050+1G>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 553754). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 02, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at