15-42390033-GGATA-GCTT
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_000070.3(CAPN3):c.883_886delGATAinsCTT(p.Asp295LeufsTer57) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000070.3 frameshift, missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.883_886delGATAinsCTT | p.Asp295LeufsTer57 | frameshift_variant, missense_variant | Exon 6 of 24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.883_886delGATAinsCTT | p.Asp295LeufsTer57 | frameshift_variant, missense_variant | Exon 6 of 23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.801+938_801+941delGATAinsCTT | intron_variant | Intron 5 of 20 | NP_775110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.883_886delGATAinsCTT | p.Asp295LeufsTer57 | frameshift_variant, missense_variant | Exon 6 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*679_*682delGATAinsCTT | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*679_*682delGATAinsCTT | 3_prime_UTR_variant | Exon 10 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2
This sequence change creates a premature translational stop signal (p.Asp295Leufs*57) 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 (rs764874721, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16141003, 16650086, 17994539, 22057634). This variant is also known as c.[883_884GA>CT; 887delA]. For these reasons, this variant has been classified as Pathogenic. -
- -
not provided Pathogenic:2
The c.883_886delGATAinsCTT variant has been previously reported in multiple individuals with suspected LGMD who had absent calpain-3 protein on western blot analysis (Todorova et al., 2005; Krahn et al., 2006; Guglieri et al., 2008); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15733273, 16141003, 17994539, 30028523, 30919934, 16650086, 15689361, 26404900, 31788660) -
- -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
- -
Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at