15-42410645-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000070.3(CAPN3):c.2242C>T(p.Arg748Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000868 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R748R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000070.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.2242C>T | p.Arg748Ter | stop_gained | 21/24 | ENST00000397163.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.2242C>T | p.Arg748Ter | stop_gained | 21/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151884Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251104Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135722
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461646Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727120
GnomAD4 genome ? AF: 0.0000198 AC: 3AN: 151884Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2AN XY: 74168
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Arg748*) 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 (rs768090444, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 12461690, 16971480, 17157502, 18055493). ClinVar contains an entry for this variant (Variation ID: 283259). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 06, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 24, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP4. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 01, 2022 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with LGMD, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 16, 2019 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 13, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at