rs766334893
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000070.3(CAPN3):c.1027G>T(p.Glu343Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000070.3 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1027G>T | p.Glu343Ter | stop_gained, splice_region_variant | 7/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.1027G>T | p.Glu343Ter | stop_gained, splice_region_variant | 7/23 | ||
CAPN3 | NM_173087.2 | c.883G>T | p.Glu295Ter | stop_gained, splice_region_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1027G>T | p.Glu343Ter | stop_gained, splice_region_variant | 7/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250884Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135652
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461222Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726942
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 24, 2018 | The E343X variant in the CAPN3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E343X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret E343X as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2018 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Baylor Genetics | Jul 10, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Glu343*) 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 (rs766334893, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 497182). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at