chr15-42410982-AG-TCATCT

Variant names:

• chr15-42410982-AG-TCATCT
• rs1555423217
• NM_000070.3:c.2362_2363delAGinsTCATCT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP4_Strong PP1 PM2_Supporting PM3_Strong PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2362_2363delinsTCATCT p.(Arg788SerfsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 23/24 that may cause loss of function of the protein, however, it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been detected in at least 30 individuals with limb girdle muscular dystrophy, including in a homozygous state in one patient (0.5 pts, PMID:18337726), in trans with a pathogenic variant in at least one patient (c.643_663del p.(Ser215_Gly221del), 1.0 pt, PMID:9150160), and in unknown phase with a pathogenic variant (c.223dup p.(Tyr75LeufsTer5), 0.5 pts, PMID:30564623, LOVD Individual #00220184) (PM3_Strong). At least one patient with this variant displayed a clinical suspicion of limb girdle muscular dystrophy and absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID:18337726). The variant has also been reported to segregate with LGMD in one affected family member (PP1; PMID:9150160). 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_Moderate, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127307/MONDO:0015152/187

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 5.91
• Publications: 5 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 12 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.
• PP1: 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.2362_2363delAGinsTCATCT	p.Arg788SerfsTer14	frameshift missense	Exon 22 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.2344_2345delAGinsTCATCT	p.Arg782SerfsTer14	frameshift missense	Exon 21 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.2086_2087delAGinsTCATCT	p.Arg696SerfsTer14	frameshift missense	Exon 19 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2362_2363delAGinsTCATCT	p.Arg788SerfsTer14	frameshift missense	Exon 22 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.2344_2345delAGinsTCATCT	p.Arg782SerfsTer14	frameshift missense	Exon 21 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.2086_2087delAGinsTCATCT	p.Arg696SerfsTer14	frameshift missense	Exon 19 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
3	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (4)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
1	-	-	Myositis, eosinophilic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=0/200	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555423217; hg19: chr15-42703180;