rs121434548

chr15-42401755-G-Achr15-42401755-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000070.3(CAPN3):c.1469G>A(p.Arg490Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,044 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R490W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.86

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]

ACMG classification

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 0 benign, 6 uncertain in NM_000070.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42401754-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 166790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 15-42401755-G-A is Pathogenic according to our data. Variant chr15-42401755-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42401755-G-A is described in Lovd as [Pathogenic]. Variant chr15-42401755-G-A is described in Lovd as [Pathogenic]. Variant chr15-42401755-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1469G>A	p.Arg490Gln	missense_variant	11/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1469G>A	p.Arg490Gln	missense_variant	11/23
CAPN3	NM_173087.2	c.1325G>A	p.Arg442Gln	missense_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1469G>A	p.Arg490Gln	missense_variant	11/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251152 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135736

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727200

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

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: 0.000132

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 490 of the CAPN3 protein (p.Arg490Gln). This variant is present in population databases (rs121434548, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9266733, 14578192, 15221789, 21984748, 22378277, 27023906, 27431290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as NM_173087:c.1325G>A. ClinVar contains an entry for this variant (Variation ID: 17622). 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. This variant disrupts the p.Arg490 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 14578192, 15221789, 16372320, 16971480, 17157502, 18563459, 18854869, 19015733, 19226146, 21204801, 25135358, 25252031, 26632398, 27055500). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg490Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006860% (19/276950) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434548). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg490Gln variant in CAPN3 has been reported in 11 individuals with LGMD and segregated with disease in 2 affected relatives from 1 family (PMID: 16971480, 22378277, 16411092). The presence of this variant in combination with 4 variants (2 reported pathogenic, 2 reported in the literature only) and in 5 individuals with LGMD increases the likelihood that the p.Arg490Gln variant is pathogenic (Variation ID: 17621, 289644). In vitro functional studies provide some evidence that the p.Arg490Gln variant may impact protein function by impairing autolytic activity (PMID: 16971480). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for p.Arg490Gln in an autosomal recessive manner based on evidence from function studies and multiple occurrences with pathogenic CAPN3 variants in individuals with hearing loss). ACMG/AMP Criteria applied: PM2, PP3, PP1, PM3_Strong, PS3 (Richards 2015). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 28, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2021	Published functional studies demonstrate disruption of protein function (Fanin et al., 2003); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17994539, 18055493, 22378277, 16411092, 16141003, 21984748, 9266733, 15725583, 16650086, 15221789, 10330340, 14578192, 20635405, 27023906, 27431290, 16971480, 34426522, 30028523, 32140910, 31589614, 32721234, 32528171) -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 22, 2023

- -

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

Mar 11, 2022

Variant summary: CAPN3 c.1469G>A (p.Arg490Gln) results in a conservative amino acid change located in the Calpain subdomain III (IPR033883) 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 6.8e-05 in 251152 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.1469G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Richard_1999, Fanin_2007). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant impairs calpain-3 autolytic activity (Fanin_2007). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Jan 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.74	T
REVEL	Pathogenic	0.94
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.96
MutPred		0.94		.;Loss of MoRF binding (P = 0.0262);.;Loss of MoRF binding (P = 0.0262);
MVP		0.97
MPC		0.68
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.90
gMVP		0.76

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

Other links and lift over

dbSNP: rs121434548; hg19: chr15-42693953;