rs150226817
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6
The NM_000070.3(CAPN3):c.1543G>A(p.Gly515Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,094 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00032 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 1 hom. )
Consequence
CAPN3
NM_000070.3 missense
NM_000070.3 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 9.92
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 Uncertain_significance. Variant got 1 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
BP6
Variant 15-42402800-G-A is Benign according to our data. Variant chr15-42402800-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254861.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1543G>A | p.Gly515Arg | missense_variant | 13/24 | ENST00000397163.8 | NP_000061.1 | |
CAPN3 | NM_024344.2 | c.1543G>A | p.Gly515Arg | missense_variant | 13/23 | NP_077320.1 | ||
CAPN3 | NM_173087.2 | c.1399G>A | p.Gly467Arg | missense_variant | 12/21 | NP_775110.1 | ||
CAPN3 | NM_173088.2 | c.7G>A | p.Gly3Arg | missense_variant | 2/13 | NP_775111.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1543G>A | p.Gly515Arg | missense_variant | 13/24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
ENSG00000258461 | ENST00000495723.1 | n.*1997G>A | non_coding_transcript_exon_variant | 16/26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*1997G>A | 3_prime_UTR_variant | 16/26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes AF: 0.000309 AC: 47AN: 152150Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251386Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135876
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GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461826Hom.: 1 Cov.: 33 AF XY: 0.0000935 AC XY: 68AN XY: 727216
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GnomAD4 genome AF: 0.000322 AC: 49AN: 152268Hom.: 1 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74462
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2021 | 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: 33250842) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 10, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2022 | Variant summary: CAPN3 c.1543G>A (p.Gly515Arg) results in a non-conservative amino acid change located in the subdomain III (IPR033883) 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 0.00031 in 150922 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0011 including 1 homozygote (in the gnomAD database, v3.1 genomes dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no clear conclusions about variant significance. The variant, c.1543G>A, has been reported in the literature in an individual affected with proximal myopathy, who also carried a (likely) pathogenic CAPN3 variant, however the phase of these two variants was not determined (Chakravorty_2020). On the other hand, the variant was also reported in 3 individuals affected with limb-girdle muscular dystrophy (LGMD), however, two of these patients also carried two co-occurring pathogenic variants in other genes, which could explain the phenotype, while the 3rd patient carried a potentially pathogenic CAPN3 variant in cis (LOVD, PMID 30564623). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2016 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 25, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 515 of the CAPN3 protein (p.Gly515Arg). This variant is present in population databases (rs150226817, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 254861). 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. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;D;T;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;.;L;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;.;.
Vest4
MutPred
0.61
.;Gain of MoRF binding (P = 0.0404);.;Gain of MoRF binding (P = 0.0404);.;.;
MVP
MPC
0.68
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at