chr15-42408246-CA-C

Variant names:

• chr15-42408246-CA-C
• rs1555422832
• NM_000070.3:c.1838delA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM3 PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1838del p.(Lys613ArgfsTer49) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 17/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three individuals with features of limb girdle muscular dystrophy (PMID:16607617, 18055493, ClinVar SCV000953543.3 internal data communication), including confirmed in trans with a pathogenic variant (c.1079G>A p.(Trp360Ter), 1.0 pt, ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy or showed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA489885447/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 8.11
• Publications: 0 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• limb-girdle muscular dystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1838delA	p.Lys613ArgfsTer49	frameshift	Exon 16 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1820delA	p.Lys607ArgfsTer49	frameshift	Exon 15 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173088.2		c.302delA	p.Lys101ArgfsTer49	frameshift	Exon 5 of 13	NP_775111.1	P20807-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1838delA	p.Lys613ArgfsTer49	frameshift	Exon 16 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1820delA	p.Lys607ArgfsTer49	frameshift	Exon 15 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000397200.8	TSL:1	c.302delA	p.Lys101ArgfsTer49	frameshift	Exon 5 of 13	ENSP00000380384.4	P20807-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461540 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727076

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111810

Other (OTH) AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555422832; hg19: chr15-42700444;