chr15-42401810-G-A

Variant names:

• chr15-42401810-G-A
• rs886043432
• NM_000070.3:c.1524G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_Strong PP3 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1524G>A variant in CAPN3 is a synonymous (silent) variant (p.Glu508=) that affects the last nucleotide of exon 11. This variant has been detected in at least seven individuals with LGMD (PMID:26404900, 17236769, 17994539, 16141003, 32528171; ClinVar SCV001423802.2 internal data communication). Of those individuals, at least three were compound heterozygous, and in at least two, the variant was confirmed in trans with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 2.0 pts, PMID:17236769, 17994539). In addition, at least one individual was homozygous for the variant (0.5 pts, PMID:17994539) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3 protein, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID:17236769). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The SpliceAI prediction score for this variant is 0.66 (donor loss), which is greater than the VCEP threshold of ≥ 0.50 and suggestive of an impact on splicing (PP3). 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; 01/07/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10605515/MONDO:0015152/187

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 9.92
• Publications: 1 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 10 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1524G>A	p.Glu508Glu	splice_region synonymous	Exon 11 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1524G>A	p.Glu508Glu	splice_region synonymous	Exon 11 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1380G>A	p.Glu460Glu	splice_region synonymous	Exon 10 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.1524G>A	p.Glu508Glu	splice_region synonymous	Exon 11 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1524G>A	p.Glu508Glu	splice_region synonymous	Exon 11 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1380G>A	p.Glu460Glu	splice_region synonymous	Exon 10 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246438 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.84
PhyloP100		9.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 0

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

Other links and lift over

dbSNP: rs886043432; hg19: chr15-42694008;