rs758058910

Positions:

• chr15-42360096-C-A
• chr15-42360096-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000070.3(CAPN3):​c.291C>A​(p.Phe97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.0400

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42360096-C-A is Pathogenic according to our data. Variant chr15-42360096-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 548137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42360096-C-A is described in Lovd as [Pathogenic]. Variant chr15-42360096-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.20172855). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.291C>A	p.Phe97Leu	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.291C>A	p.Phe97Leu	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.291C>A	p.Phe97Leu	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.291C>A	p.Phe97Leu	missense_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5643C>A		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 04, 2024

Variant summary: CAPN3 c.291C>A (p.Phe97Leu) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 248996 control chromosomes. c.291C>A has been reported in the literature in the homozygous state in at least 2 individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, El-Khoury_2019, Mojbafan_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of detectable calpain 3 protein (example, El-Khoury_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30500922, 31937337). ClinVar contains an entry for this variant (Variation ID: 548137). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

research

Neuromuscular Diagnostic Laboratory, American University of Beirut Medical Center

Jul 15, 2017

c.291C>A (p.Phe97Leu) mutation was identified in a patient diagnosed with Limb girdle muscular dystrophy type 2A (LGMD2A). The diagnosis of LGMD2A was first suspected on the basis of a typical clinical localization of the muscle weakness and further confirmed by immunoblotting and molecular analysis. His family history is pertinent as his parents were first degree cousins, but none of his three younger brothers showed clinical evidence of similarly evolving dystrophic process. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.67	.;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0040, 0.0050	.;B;B;B
Vest4		0.41
MutPred		0.50		Gain of catalytic residue at F97 (P = 0.0048);Gain of catalytic residue at F97 (P = 0.0048);Gain of catalytic residue at F97 (P = 0.0048);Gain of catalytic residue at F97 (P = 0.0048);
MVP		0.68
MPC		0.17
ClinPred		0.81	D
GERP RS		-1.2
Varity_R		0.54
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: rs758058910; hg19: chr15-42652294;