15-42399483-A-G

Variant names:

• chr15-42399483-A-G
• rs374665929
• NM_000070.3:c.1194-9A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM3 PVS1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000070.3:c.1194-9A>G variant in CAPN3 is located in intron 9 of 23 and is expected to disrupt the canonical splice acceptor site (SpliceAI score 0.97 for acceptor loss) and create an alternative acceptor site (SpliceAI score 1.0 for acceptor gain). RNA analysis has demonstrated a splice effect of this variant, resulting in inclusion of the last eight nucleotides of intron 9, which is expected to lead to a frameshift, premature truncation, and subsequent nonsense mediated decay (PVS1_RNA). This variant has been detected in at least 9 unrelated individuals with clinical features of limb girdle muscular dystrophy (PMID:30564623, 22158424, 12461690, 18055493, 25135358, 10330340, 11525884; LOVD CAPN3_000088; ClinVar SCV003922313.1), including in a homozygous state (0.75 pts) (PMID:12461690, 11525884) and in unknown phase with a pathogenic variant (c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV003922313.1 (PM3). At least one individual with this variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PP4). The minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113748 chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (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; 03/18/2025): PVS1_RNA, PM3, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347487/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Scores: Splicing: ADA: 0.9900
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: -0.0700
• Publications: 10 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.
• 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.1194-9A>G		intron	N/A	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1194-9A>G		intron	N/A	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1050-9A>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.1194-9A>G		intron	N/A	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1194-9A>G		intron	N/A	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1050-9A>G		intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151774 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1459346 Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 12 AN XY: 726242

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1109784

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151774 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74106

African (AFR) AF: 0.0000242 AC: 1 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00000947 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	23
DANN	Benign	0.63
PhyloP100		-0.070
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.97		Position offset: 9

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

Other links and lift over

dbSNP: rs374665929; hg19: chr15-42691681;