Genetic Variant CAPN3:c.1993-1G>A (chr15-42409786-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM3PP4_ModeratePVS1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1993-1G>A variant in CAPN3 occurs within the -1/2 dinucleotide splice acceptor site of intron 17. This variant is predicted to abolish the consensus splice acceptor site, with a SpliceAI score of 0.99, and strengthen an alternative site 1 bp away, with a SpliceAI score of 1.0. Use of the alternative acceptor site or skipping of exon 18, which is out of frame, would be expected to disrupt the reading frame, leading to nonsense mediated decay in a gene in which loss of function is an established mechanism of disease (PVS1). This variant has been reported in at least six patients with clinical features consistent with LGMD (PMID:30564623, 26404900, 18055493; LOVD CAPN3_000288), including in a homozygous state in one proband from a family without reported consanguinity (0.5 pts, PMID:30564623, LOVD Individual #00220357) and in unknown phase with a pathogenic variant in one individual (c.550del, 0.5 pts, PMID:30564623, LOVD Individual #00219523) (PM3). At least one individual with this variant and a second presumed diagnostic variant in CAPN3 had a clinical suspicion of LGMD and significantly reduced calpain-3 protein expression on western blot, which is specific for CAPN3-related LGMD (PMID:18055493; PP4_Moderate). The filtering allele frequency of this variant is 0.000030594 in the European (non-Finnish) population in gnomAD v4.1.0 (24/1103246 exomes), 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; 05/03/2025): PVS1, PM3, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511659/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 10.0

Publications

3 publications found

Variant links:

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)

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Specifications for CAPN3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CAPN3	NM_000070.3	MANE Select	c.1993-1G>A	splice_acceptor intron	N/A	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.1975-1G>A	splice_acceptor intron	N/A	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.1717-1G>A	splice_acceptor intron	N/A	NP_775110.1	P20807-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1993-1G>A	splice_acceptor intron	N/A	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.1975-1G>A	splice_acceptor intron	N/A	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.1717-1G>A	splice_acceptor intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

149284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000491

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:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251406

AF XY:

0.00000736

show subpopulations

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1449130

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

720688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33092

American (AMR)

AF:

0.00

AC:

AN:

44290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25680

East Asian (EAS)

AF:

0.00

AC:

AN:

38748

South Asian (SAS)

AF:

0.00

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000218

AC:

AN:

1103246

Other (OTH)

AF:

0.00

AC:

AN:

59526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000268

AC:

AN:

149284

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72706

show subpopulations

African (AFR)

AF:

0.0000491

AC:

AN:

40768

American (AMR)

AF:

0.00

AC:

AN:

14904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

4944

South Asian (SAS)

AF:

0.00

AC:

AN:

4658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

67300

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000226

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2A (3)

not provided (3)

Autosomal recessive limb-girdle muscular dystrophy (1)

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

PhyloP100

GERP RS

4.9

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

DS_AL_spliceai

1.0

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over