rs369552114

Variant names:

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):

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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.1993-1G>A		splice_acceptor_variant, intron_variant	Intron 17 of 23	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.1993-1G>A	splice_acceptor_variant, intron_variant	Intron 17 of 23	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.-3-1G>A	splice_acceptor_variant, intron_variant	Intron 4 of 10			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.-3-1G>A	splice_acceptor_variant, intron_variant	Intron 4 of 10			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.-3-1G>A	splice_acceptor_variant, intron_variant	Intron 5 of 11			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.-3-1G>A	splice_acceptor_variant, intron_variant	Intron 4 of 10			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.-100-1G>A	splice_acceptor_variant, intron_variant	Intron 4 of 10			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2429-1G>A	splice_acceptor_variant, intron_variant	Intron 19 of 25	2		ENSP00000492063.1	A0A1W2PQD3

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

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 17 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is present in population databases (rs369552114, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 18055493; internal data). ClinVar contains an entry for this variant (Variation ID: 282494). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jul 15, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 02, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Pathogenic:3

Jan 30, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15689361, 32528171, 10330340, 26404900, 18055493) -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Sep 13, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

May 03, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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. -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over