chr15-42401803-T-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000070.3(CAPN3):c.1517T>C(p.Ile506Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
CAPN3
NM_000070.3 missense
NM_000070.3 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.96
Genes affected
CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 pathogenic changes around while only 0 benign (100%) in NM_000070.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952
PP5
Variant 15-42401803-T-C is Pathogenic according to our data. Variant chr15-42401803-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 502152.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}. Variant chr15-42401803-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1517T>C | p.Ile506Thr | missense_variant | 11/24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.1517T>C | p.Ile506Thr | missense_variant | 11/23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.1373T>C | p.Ile458Thr | missense_variant | 10/21 | NP_775110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1517T>C | p.Ile506Thr | missense_variant | 11/24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*1313T>C | non_coding_transcript_exon_variant | 15/26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*1313T>C | 3_prime_UTR_variant | 15/26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 29, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 24, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 502152). This missense change has been observed in individual(s) with clinical features of autosomal recessive CAPN3-related conditions (PMID: 25987458). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 506 of the CAPN3 protein (p.Ile506Thr). - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 24, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2024 | Variant summary: CAPN3 c.1517T>C (p.Ile506Thr) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1517T>C has been reported in the literature in a compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Dai_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25987458). ClinVar contains an entry for this variant (Variation ID: 502152). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;D;D
Vest4
MutPred
0.80
.;Loss of stability (P = 0.0313);.;Loss of stability (P = 0.0313);
MVP
MPC
0.71
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at