rs147764579

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000070.3(CAPN3):c.1466G>A(p.Arg489Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,902 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. R489W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 9.86

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]

CAPN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42401751-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

PP5

Variant 15-42401752-G-A is Pathogenic according to our data. Variant chr15-42401752-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42401752-G-A is described in Lovd as [Pathogenic]. Variant chr15-42401752-G-A is described in Lovd as [Pathogenic]. Variant chr15-42401752-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.1466G>A	p.Arg489Gln	missense_variant	11/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.1466G>A	p.Arg489Gln	missense_variant	11/23
CAPN3	NM_173087.2 linkuse as main transcript	c.1322G>A	p.Arg441Gln	missense_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1466G>A	p.Arg489Gln	missense_variant	11/24	1	NM_000070.3	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251278

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000145

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2019	Published functional studies demonstrate a damaging effect where normal autocatalytic calpain-3 activity was lost (Fanin et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in two families from Reunion Island with LGMD and observed in an additional patient with LGMD who harbored a pathogenic variant on the opposite allele (in trans) in published literature (Richard et al., 1999; Fanin et al., 2003); This variant is associated with the following publications: (PMID: 16884488, 16971480, 17236769, 10330340, 14578192, 17994539, 15221789, 18854869, 30919934, 32668095) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	May 22, 2024	PM2_Supporting: the highest population allele frequency in gnomAD v4.0 is 0.0006577 (0.06577%; 4/6082 alleles in Middle Eastern population) and there are no homozygous observations. PM1 not met: pathogenic variants are distributed throughout the protein. PP3_moderate: REVEL score is 0.881. PM3 Met: 1.75 points awarded for 4 proband compound heterozygous occurrences of variant (not confirmed in trans) (PMID: 30919934, 14578192). PM5 met: Other variants that disrupt this Arg residue known to be pathogenic (PMID: 9762961, 16141003, 25135358, 27708273). PS3_Supporting: Functional studies show CAPN3 Arg489Gln variant results in loss of normal autocatalytic calpain-3 activity (PMID:14578192) and a shorter CAPN3 transcript due to predicted exon skipping by minigene assay (PMID:32668095). PS4_Supporting: Variant identified in 3 probands with consistent phenotype for disorder (PMID: 10330340, 31931849). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 26, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 15, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 489 of the CAPN3 protein (p.Arg489Gln). This variant is present in population databases (rs147764579, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 14578192, 17236769, 30919934). ClinVar contains an entry for this variant (Variation ID: 289644). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg489 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9762961, 16141003, 25135358, 27708273). 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. -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 15, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2022

Variant summary: CAPN3 c.1466G>A (p.Arg489Gln) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251278 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.1466G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Milic_2007, Bevilacqua_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

CAPN3-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

The CAPN3 c.1466G>A variant is predicted to result in the amino acid substitution p.Arg489Gln. This variant has been repeatedly reported in the compound heterozygous or homozygous state in individuals with limb-girdle muscular dystrophy (Richard et al. 1999. PubMed ID: 10330340; Fanin et al. 2003. PubMed ID: 14578192; Supp. Table 1 in Ten Dam et al. 2019. PubMed ID: 30919934; https://databases.lovd.nl/shared/genes/CAPN3). Functional studies indicate this variant disrupts the normal autocatalytic activity (Fanin et al. 2003. PubMed ID: 14578192). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-42693950-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;.;.;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.5

.;M;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.8

.;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0090

.;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.94

MVP

0.95

MPC

0.68

ClinPred

0.74

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.77

gMVP

0.73

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over