rs121434547

chr15-42392649-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5 PP3_Moderate PP5_Very_Strong

The NM_000070.3(CAPN3):c.956C>T(p.Pro319Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,198 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. P319R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.80

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 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42392649-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2913353.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 15-42392649-C-T is Pathogenic according to our data. Variant chr15-42392649-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42392649-C-T is described in Lovd as [Pathogenic]. Variant chr15-42392649-C-T is described in Lovd as [Pathogenic]. Variant chr15-42392649-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.956C>T	p.Pro319Leu	missense_variant	7/24	ENST00000397163.8
CAPN3	NM_024344.2	c.956C>T	p.Pro319Leu	missense_variant	7/23
CAPN3	NM_173087.2	c.812C>T	p.Pro271Leu	missense_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.956C>T	p.Pro319Leu	missense_variant	7/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251154 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461030 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

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: 0.00

Alfa AF: 0.0000590 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 17, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 319 of the CAPN3 protein (p.Pro319Leu). This variant is present in population databases (rs121434547, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 30056071, 30919934, 34602496). ClinVar contains an entry for this variant (Variation ID: 17617). 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 95%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2015	The P319L variant in the CAPN3 gene has been reported previously in the compound heterozygous state inmultiple affected family members and one unrelated individual with limb-girdle muscular dystrophy type 2A(Richard et al., 1997; Piluso et al., 2005). The P319L variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however,data from ethnically-matched control individuals were not available to assess for a population-specific benignvariant. The P319L substitution is a semi-conservative amino acid substitution, which may impact secondaryprotein structure as these residues differ in some properties. This substitution occurs at a position that isconserved through mammals. In addition, missense variants in nearby residues (V320F, Y322H) have beenreported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson etal., 2014), supporting the functional importance of this region of the protein. We interpret P319L as a pathogenic variant. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.62	T
REVEL	Pathogenic	0.65
Sift4G	Uncertain	0.055	T;D;T;D
Polyphen		0.81, 0.32, 0.85	.;P;B;P
Vest4		0.80
MutPred		0.88		.;Loss of loop (P = 0.0374);.;Loss of loop (P = 0.0374);
MVP		0.96
MPC		0.23
ClinPred		0.48	T
GERP RS		4.4
Varity_R		0.24
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs121434547; hg19: chr15-42684847; COSMIC: COSV58819346;