15-42399631-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000070.3(CAPN3):c.1333G>T(p.Gly445*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,300 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 (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000070.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1333G>T | p.Gly445* | stop_gained | Exon 10 of 24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.1333G>T | p.Gly445* | stop_gained | Exon 10 of 23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.1189G>T | p.Gly397* | stop_gained | Exon 9 of 21 | NP_775110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1333G>T | p.Gly445* | stop_gained | Exon 10 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*1129G>T | non_coding_transcript_exon_variant | Exon 14 of 26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*1129G>T | 3_prime_UTR_variant | Exon 14 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1453300Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 721774
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Qualitative or quantitative defects of calpain Pathogenic:1
The homozygous p.Gly445Ter variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (PMID: 32528171). The p.Gly445Ter variant in CAPN3 has not been previously reported in individuals with autosomal recessive limb-girdle muscular dystrophy 1. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 358, which is predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 1. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.