rs587780291
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000070.3(CAPN3):c.371G>C(p.Gly124Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,802 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). Synonymous variant affecting the same amino acid position (i.e. G124G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.371G>C | p.Gly124Ala | missense_variant | 2/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.371G>C | p.Gly124Ala | missense_variant | 2/23 | ||
CAPN3 | NM_173087.2 | c.371G>C | p.Gly124Ala | missense_variant | 2/21 | ||
LOC105370794 | XR_932178.3 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.371G>C | p.Gly124Ala | missense_variant | 2/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251394Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135856
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460802Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726766
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 124 of the CAPN3 protein (p.Gly124Ala). This variant is present in population databases (rs587780291, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of CAPN3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 128571). 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 with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 07, 2013 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 29, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2022 | The c.371G>C (p.G124A) alteration is located in exon 2 (coding exon 2) of the CAPN3 gene. This alteration results from a G to C substitution at nucleotide position 371, causing the glycine (G) at amino acid position 124 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at