rs2241827

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1537-48T>C variant in CAPN3 is an intronic variant. The filtering allele frequency for this variant is 0.9344 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 31266/33150 African/African American exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold ≥0.003 for BA1 (BA1). The SpliceAI prediction of 0.00 indicates no splicing impact and does not exceed the LGMD VCEP threshold of ≤0.05 (BP4). This variant is also not in a splice region (BP7). In summary, this variant meets the criteria to be classified as Benign 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; 03/14/2025): BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145717/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.76 ( 44598 hom., cov: 32)

Exomes 𝑓: 0.70 ( 353734 hom. )

Consequence

CAPN3
NM_000070.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: -2.08

Publications

7 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: Benign. The variant received -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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.1537-48T>C	intron	N/A	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.1537-48T>C	intron	N/A	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.1393-48T>C	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.1537-48T>C	intron	N/A	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.1537-48T>C	intron	N/A	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.1393-48T>C	intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.755

AC:

114785

AN:

151966

Hom.:

44544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.934

Gnomad AMI

AF:

0.785

Gnomad AMR

AF:

0.705

Gnomad ASJ

AF:

0.773

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.696

Gnomad FIN

AF:

0.645

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.703

Gnomad OTH

AF:

0.757

GnomAD2 exomes

AF:

0.682

AC:

168544

AN:

247040

AF XY:

0.687

show subpopulations

Gnomad AFR exome

AF:

0.935

Gnomad AMR exome

AF:

0.608

Gnomad ASJ exome

AF:

0.765

Gnomad EAS exome

AF:

0.423

Gnomad FIN exome

AF:

0.633

Gnomad NFE exome

AF:

0.706

Gnomad OTH exome

AF:

0.700

GnomAD4 exome

AF:

0.696

AC:

1006273

AN:

1444820

Hom.:

353734

Cov.:

AF XY:

0.697

AC XY:

502013

AN XY:

719856

show subpopulations

African (AFR)

AF:

0.943

AC:

31266

AN:

33150

American (AMR)

AF:

0.625

AC:

27763

AN:

44456

Ashkenazi Jewish (ASJ)

AF:

0.767

AC:

19965

AN:

26030

East Asian (EAS)

AF:

0.413

AC:

16336

AN:

39538

South Asian (SAS)

AF:

0.707

AC:

60690

AN:

85846

European-Finnish (FIN)

AF:

0.633

AC:

33413

AN:

52766

Middle Eastern (MID)

AF:

0.778

AC:

4303

AN:

5530

European-Non Finnish (NFE)

AF:

0.702

AC:

770160

AN:

1097788

Other (OTH)

AF:

0.710

AC:

42377

AN:

59716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

17743

35485

53228

70970

88713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19334

38668

58002

77336

96670

<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:

0.755

AC:

114895

AN:

152084

Hom.:

44598

Cov.:

AF XY:

0.750

AC XY:

55712

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.935

AC:

38786

AN:

41504

American (AMR)

AF:

0.704

AC:

10756

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.773

AC:

2685

AN:

3472

East Asian (EAS)

AF:

0.428

AC:

2213

AN:

5168

South Asian (SAS)

AF:

0.696

AC:

3350

AN:

4810

European-Finnish (FIN)

AF:

0.645

AC:

6818

AN:

10578

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.703

AC:

47766

AN:

67964

Other (OTH)

AF:

0.751

AC:

1587

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1357

2713

4070

5426

6783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.728

Hom.:

56891

Bravo

AF:

0.766

Asia WGS

AF:

0.567

AC:

1972

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Autosomal recessive limb-girdle muscular dystrophy (1)

Autosomal recessive limb-girdle muscular dystrophy type 2A (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.50

(source)

DANN

Benign

0.34

PhyloP100

-2.1

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over