15-42410925-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):​c.2305C>T​(p.Arg769Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,784 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R769P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

13
4
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.04
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 9 uncertain in NM_000070.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-42410926-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 15-42410925-C-T is Pathogenic according to our data. Variant chr15-42410925-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410925-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42410925-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CAPN3NM_000070.3 linkuse as main transcriptc.2305C>T p.Arg769Trp missense_variant 22/24 ENST00000397163.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CAPN3ENST00000397163.8 linkuse as main transcriptc.2305C>T p.Arg769Trp missense_variant 22/241 NM_000070.3 P2P20807-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251388
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135852
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1461784
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.0000189
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin BerlinSep 22, 2022- -
Likely pathogenic, no assertion criteria providedclinical testingCounsylMay 16, 2017- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 17, 2023This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 769 of the CAPN3 protein (p.Arg769Trp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 20517216, 26060040, 27066551, 28403181). ClinVar contains an entry for this variant (Variation ID: 282411). 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.Arg769 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 7762565, 7795603, 12461690, 14645990). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 02, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 12, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 25, 2020The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, flagged submissionclinical testingBaylor GeneticsSep 13, 2023- -
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 26, 2023Variant summary: CAPN3 c.2305C>T (p.Arg769Trp) results in a non-conservative amino acid change located in the EF hand domain (IPR002048) 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 1.2e-05 in 251388 control chromosomes (gnomAD). c.2305C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy (example: Nallamilli_2018, Yu_2017, Tian_2015). Other variant affecting the same codon has been classified pathogenic in ClinVar (p.Arg769Gln CV ID 17613) The following publications have been ascertained in the context of this evaluation (PMID: 30564623, 27066551, 28403181). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc TauliApr 26, 2021PP5_strong;PM1_moderate;PM2_supporting;PM3_moderate;PM5_moderate;PP3_supporting;BP1_supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
T;.;.;D;.;.;.;.;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;.;D;.;D;.
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
.;.;.;H;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-7.0
.;D;D;D;D;D;D;.;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
.;D;D;D;D;D;D;.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;.;.;.;.;.;.;.
Vest4
0.98
MutPred
0.93
.;.;.;Gain of methylation at K773 (P = 0.0579);.;.;.;.;.;.;.;
MVP
0.99
MPC
0.64
ClinPred
1.0
D
GERP RS
3.5
Varity_R
0.88
gMVP
0.94

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: rs868791726; hg19: chr15-42703123; API