rs148044781
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000070.3(CAPN3):c.1505T>C(p.Ile502Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. I502V) 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 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1505T>C | p.Ile502Thr | missense_variant | 11/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.1505T>C | p.Ile502Thr | missense_variant | 11/23 | ||
CAPN3 | NM_173087.2 | c.1361T>C | p.Ile454Thr | missense_variant | 10/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1505T>C | p.Ile502Thr | missense_variant | 11/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000237 AC: 36AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000148 AC: 37AN: 250192Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 135284
GnomAD4 exome AF: 0.000443 AC: 648AN: 1461498Hom.: 0 Cov.: 33 AF XY: 0.000435 AC XY: 316AN XY: 727010
GnomAD4 genome ? AF: 0.000237 AC: 36AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | CAPN3: PM1, PM5, PM2:Supporting, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 09, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 27, 2018 | The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22926650, 26810512, 10330340, 30564623, 30919934, 32994280, 31555977, 35734998) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 17, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 20, 2018 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 22, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 502 of the CAPN3 protein (p.Ile502Thr). This variant is present in population databases (rs148044781, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of autosomal recessive CAPN3-related conditions (PMID: 10330340, 26810512, 30919934; Invitae). ClinVar contains an entry for this variant (Variation ID: 282512). 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%. This variant disrupts the p.Ile502 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 18337726), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2023 | Variant summary: CAPN3 c.1505T>C (p.Ile502Thr) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250192 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00015 vs 0.0032), allowing no conclusion about variant significance. c.1505T>C has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Lahoria_2016, Ten Dam_2019, Barp_2020, Nallamilli_2018, Richard_1999, Becker_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31555977, 26810512, 30564623, 10330340, 30919934, 35135626). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely pathogenic, n=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2014 | The c.1505T>C (p.I502T) alteration is located in exon 11 (coding exon 11) of the CAPN3 gene. This alteration results from a T to C substitution at nucleotide position 1505, causing the isoleucine (I) at amino acid position 502 to be replaced by a threonine (T). This nucleotide position is conserved in available vertebrate species.This amino acid position is conserved in available vertebrate species. 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