dbSNP rs727503837: CAPN3:p.Phe200_Leu204del (chr15-42387850-AGTTCTGGAGTGCTCT-A) – ACMG Classification: Pathogenic (9 pts)

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4_StrongPM4PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.598_612del variant in CAPN3 is predicted to cause a change in the length of the protein due to an in-frame deletion of five amino acids in a non-repeat region, p.(Phe200_Leu204del) (PM4). This variant has been detected in at least 24 individuals with LGMD2A (PMID:23821418, 34720847, 25135358, 34863162, 37688281,16372320, 30564623). At least six patients were compound heterozygous for c.598_612del and a pathogenic variant (c.550del or c.1746-20C>G, 6.0 pts, PMID:16372320, 23821418, 34720847), and three patients were homozygous (1.0 pt, PMID:23821418) (PM3_Very Strong). At least one patient with this variant and a second CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression, which is highly consistent with CAPN3-related LGMD (PMID:16372320; PP4_Strong). The filtering allele frequency (the upper threshold of the 95% CI of 20/1112002 exome chromosomes) is 0.000026 for the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets 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): PM4, PM3_Very Strong, PP4_Strong, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA346121/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 10.0

Publications

6 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

Classification was made for transcript

Our verdict: Pathogenic. The variant received 9 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.

PM4

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	HGVSp	Effect	Exon Rank	Protein	UniProt
CAPN3	NM_000070.3	MANE Select	c.598_612delTTCTGGAGTGCTCTG	p.Phe200_Leu204del	conservative_inframe_deletion	Exon 4 of 24	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.598_612delTTCTGGAGTGCTCTG	p.Phe200_Leu204del	conservative_inframe_deletion	Exon 4 of 23	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.598_612delTTCTGGAGTGCTCTG	p.Phe200_Leu204del	conservative_inframe_deletion	Exon 4 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.598_612delTTCTGGAGTGCTCTG	p.Phe200_Leu204del	conservative_inframe_deletion	Exon 4 of 24	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.598_612delTTCTGGAGTGCTCTG	p.Phe200_Leu204del	conservative_inframe_deletion	Exon 4 of 23	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.598_612delTTCTGGAGTGCTCTG	p.Phe200_Leu204del	conservative_inframe_deletion	Exon 4 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251464

AF XY:

0.0000368

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461882

Hom.:

AF XY:

0.0000206

AC XY:

AN XY:

727242

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000725325), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.370

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:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

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

Autosomal recessive limb-girdle muscular dystrophy (1)

CAPN3-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over