15-42399607-C-G

Variant names:

• chr15-42399607-C-G
• NM_000070.3:c.1309C>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000070.3(CAPN3):​c.1309C>G​(p.Arg437Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R437C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.84

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42399607-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 15-42399607-C-G is Pathogenic according to our data. Variant chr15-42399607-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2680368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399607-C-G is described in Lovd as [Pathogenic]. Variant chr15-42399607-C-G is described in Lovd as [Pathogenic]. Variant chr15-42399607-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1309C>G	p.Arg437Gly	missense_variant	Exon 10 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1309C>G	p.Arg437Gly	missense_variant	Exon 10 of 23		NP_077320.1
CAPN3	NM_173087.2	c.1165C>G	p.Arg389Gly	missense_variant	Exon 9 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1309C>G	p.Arg437Gly	missense_variant	Exon 10 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1105C>G		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1105C>G		3_prime_UTR_variant	Exon 14 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Apr 23, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAPN3 c.1309C>G (p.Arg437Gly) results in a non-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 was absent in 249478 control chromosomes. c.1309C>G has been reported in the homozygous or compound heterozygous state in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Hauerslev_2012, Yu_2017, Guglieri_2008). In one individual, this variant was in trans with a pathogenic truncating variant (Yu_2017). These data indicate that the variant is very likely to be associated with disease. Samples of skeletal muscle tissue from homozygous individuals either lacked or had very low calpain-3 protein (approximately 5-20% of controls) as determined by immunohistochemistry and Western blotting (e.g. Hauerslev_2012, Guglieri_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18337726, 17994539, 22443334, 28403181). ClinVar contains an entry for this variant (Variation ID: 2680368). Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1

Mar 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg437 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330340, 15221789, 16141003, 18563459, 18854869, 20044116, 26404900, 27081656). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 17994539, 18337726, 22443334). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 437 of the CAPN3 protein (p.Arg437Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.6	.;M;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	.;D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.054	.;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		1.0, 1.0	.;D;D;D
Vest4		0.97
MutPred		0.85		.;Loss of MoRF binding (P = 0.0608);.;Loss of MoRF binding (P = 0.0608);
MVP		0.96
MPC		0.71
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.60
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42691805;