15-42399641-G-T

Position:

• chr15-42399641-G-T

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.1343G>T​(p.Arg448Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr15-42399640-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 15-42399641-G-T is Pathogenic according to our data. Variant chr15-42399641-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1180840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399641-G-T is described in Lovd as [Pathogenic]. Variant chr15-42399641-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1343G>T	p.Arg448Leu	missense_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1343G>T	p.Arg448Leu	missense_variant	10/23
CAPN3	NM_173087.2	c.1199G>T	p.Arg400Leu	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1343G>T	p.Arg448Leu	missense_variant	10/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 21, 2024

- -

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

Jul 24, 2023

Variant summary: CAPN3 c.1343G>T (p.Arg448Leu) results in a non-conservative amino acid change located in the calpain large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235170 control chromosomes (gnomAD). c.1343G>T has been reported in the literature as a biallelic genotype in individuals affected with autosomal recessive Limb-Girdle Muscular Dystrophy, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g. Luo_2012, Dai_2015, Yu_2017, Chakravorty_2021, Zhong_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, it has been reported in a homozygous individual who exhibited a loss of calpain-3 expression as determined by Western blotting (Feng_2018) and there are multiple other missense variants affecting the same amino acid (e.g. R448G, R448C, R448H) which have been classified as pathogenic, suggesting Arg448 is important for protein function and alterations to this residue are likely to be disease-causing. The following publications have been ascertained in the context of this evaluation (PMID: 33250842, 25987458, 29797799, 22926650, 28403181, 32994280). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;D
Vest4		0.96
MutPred		0.89		.;Loss of methylation at R448 (P = 0.0392);.;Loss of methylation at R448 (P = 0.0392);
MVP		0.95
MPC		0.70
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.87

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: rs863224956; hg19: chr15-42691839;