rs1555422136

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I506L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CAPN3
NM_000070.3 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 7.96
Variant links:
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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain 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: {Likely_pathogenic=2, Uncertain_significance=3}. Variant chr15-42401803-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CAPN3NM_000070.3 linkuse as main transcriptc.1517T>C p.Ile506Thr missense_variant 11/24 ENST00000397163.8
CAPN3NM_024344.2 linkuse as main transcriptc.1517T>C p.Ile506Thr missense_variant 11/23
CAPN3NM_173087.2 linkuse as main transcriptc.1373T>C p.Ile458Thr missense_variant 10/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CAPN3ENST00000397163.8 linkuse as main transcriptc.1517T>C p.Ile506Thr missense_variant 11/241 NM_000070.3 P2P20807-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 24, 2023In 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). -
Uncertain significance, criteria provided, single submitterclinical testingCounsylMay 29, 2018- -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Likely pathogenic, flagged submissionclinical testingBaylor GeneticsOct 25, 2023- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 24, 2017- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 10, 2024Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;.;D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
3.8
.;H;.;H
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.4
.;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
.;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
.;D;D;D
Vest4
0.97
MutPred
0.80
.;Loss of stability (P = 0.0313);.;Loss of stability (P = 0.0313);
MVP
0.98
MPC
0.71
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.93
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555422136; hg19: chr15-42694001; API