rs886044427
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The ENST00000397163.8(CAPN3):āc.2119G>Cā(p.Asp707His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,836 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D707G) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000397163.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.2119G>C | p.Asp707His | missense_variant | 20/24 | ENST00000397163.8 | NP_000061.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.2119G>C | p.Asp707His | missense_variant | 20/24 | 1 | NM_000070.3 | ENSP00000380349 | P2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp707 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10567047, 11525884, 25252031, 26632398). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. This variant has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 290334). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 707 of the CAPN3 protein (p.Asp707His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at