15-42386267-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000070.3(CAPN3):c.483delG(p.Ile162SerfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000070.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.483delG | p.Ile162SerfsTer17 | frameshift_variant | Exon 3 of 24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.483delG | p.Ile162SerfsTer17 | frameshift_variant | Exon 3 of 23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.483delG | p.Ile162SerfsTer17 | frameshift_variant | Exon 3 of 21 | NP_775110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.483delG | p.Ile162SerfsTer17 | frameshift_variant | Exon 3 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*279delG | non_coding_transcript_exon_variant | Exon 7 of 26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*279delG | 3_prime_UTR_variant | Exon 7 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
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.Ile162Serfs*17) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with limb girdle muscular dystrophy type 2 (PMID: 16650086). ClinVar contains an entry for this variant (Variation ID: 217156). For these reasons, this variant has been classified as Pathogenic. -
The heterozygous p.Ile162SerfsTer17 variant in CAPN3 was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD increases the likelihood that the p.Ile162SerfsTer17 variant is pathogenic. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 162 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of another pathogenic variant in one individual with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015). -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
- -
not provided Pathogenic:1
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. Moderate co-segregation with disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at