rs201892814

Variant names:

• chr15-42403721-C-G
• rs201892814
• NM_000070.3:c.1746-20C>G

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PP1_Moderate PP4_Moderate PM3 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1746-20C>G variant occurs in intron 13 of the CAPN3 gene. The filtering allele frequency for this variant is 0.006051 in gnomAD v2.1.1 European (non-Finnish) genomes (the lower threshold of the 95% CI of 172/31388), which is higher than the LGMD VCEP threshold of 0.001 for BS1; in total, three homozygous individuals are also observed. However, this variant may act as a hypomorphic allele, and the VCEP opted not to apply this code (BS1 exception). RNAseq/cDNA analysis of muscle from patients carrying one copy of the variant suggests that it results in aberrant splicing, the inclusion of various portions of intron 13, and premature truncation (PMID:20635405, 35731190). An earlier study concluded the variant does not affect splicing (PMID:17979987); however, later investigations showed that the aberrantly spliced transcripts are variably expressed and not always detectable even when splicing-specific PCR is used, possibly due to nonsense-mediated mRNA decay (PMID:20635405) (PVS1_RNA_Moderate). The c.1746-20C>G variant has been detected with a second CAPN3 variant in at least 34 individuals with LGMD (PMID:37589857, 20635405, 17979987, 17157502, 35731190), including confirmed in trans with a pathogenic variant in five cases (c.550delA p.(Thr184ArgfsTer36), 4.0 pts, PMID:20635405, 35731190; c.643_663del p.(Ser215_Gly221del): 1.0 pt, PMID:35731190) (PM3_Very Strong). The variant was also reported to co-segregate with autosomal recessive disease in four affected family members from three families (PP1_Moderate; PMID:37589857, 20635405, 35731190). Several patients with the c.1746-20C>G variant and a second CAPN3 variant displayed progressive limb girdle muscle weakness or clinical suspicion of limb-girdle muscular dystrophy as well as significantly reduced or absent expression of calpain-3, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID:20635405). While two homozygous patients with a mild phenotype have been reported (PMID:35731190), the number of apparently unaffected homozygous individuals described and present in population databases suggests this variant may show reduced penetrance in the homozygous state. 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_RNA_Moderate, PM3_Very Strong, PP1_Moderate, PP4_Moderate. The LGMD VCEP recommends careful correlation with patient phenotype and family history as well as consideration of the combined functional impact of both CAPN3 alleles when the c.1746-20C>G variant is detected in an individual with signs of limb girdle muscular dystrophy. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220343/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (14 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:8 B:2
• Conservation: PhyloP100: 0.0590
• Publications: 23 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 8 ACMG points.

• PVS1: 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.1746-20C>G		intron	N/A	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1746-20C>G		intron	N/A	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1602-20C>G		intron	N/A	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.1746-20C>G		intron	N/A	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1746-20C>G		intron	N/A	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1602-20C>G		intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00315 AC: 791 AN: 251486 AF XY: 0.00324

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00311 AC: 4534 AN: 1460084 Hom.: 14 Cov.: 30 AF XY: 0.00312 AC XY: 2268 AN XY: 726476

African (AFR) AF: 0.000179 AC: 6 AN: 33444

American (AMR) AF: 0.00105 AC: 47 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.00983 AC: 525 AN: 53386

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5760

European-Non Finnish (NFE) AF: 0.00335 AC: 3716 AN: 1110426

Other (OTH) AF: 0.00254 AC: 153 AN: 60326

GnomAD4 genome AF: 0.00309 AC: 470 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74466

African (AFR) AF: 0.000457 AC: 19 AN: 41556

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00420 Hom.: 0

Bravo AF: 0.00209

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	3	-	not provided (6)
2	2	1	Autosomal recessive limb-girdle muscular dystrophy type 2A (5)
2	1	-	Autosomal recessive limb-girdle muscular dystrophy (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
-	-	1	not specified (1)
1	-	-	Paresthesia;C0149931:Migraine;C0240914:Positive Romberg sign;C0241005:Elevated circulating creatine kinase concentration;C0311394:Difficulty walking;C4021727:EMG: neuropathic changes;C4022625:Absent muscle fiber calpain-3;C4082951:Progressive spinal muscular atrophy (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.59
PhyloP100		0.059
Mutation Taster		=24/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.13		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: rs201892814; hg19: chr15-42695919;