NM_000070.3:c.1800+21C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7BS1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1800+21C>T variant in CAPN3 is an intronic variant that does not occur in a splice region (+7/-21). The filtering allele frequency for this variant is 0.002152 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2461/1105660 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.01, which is less than the VCEP threshold of 0.05 (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511545/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

CAPN3
NM_000070.3 intron

Scores

Clinical Significance

Likely benign reviewed by expert panel B:2

Conservation

PhyloP100: 0.110

Publications

2 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: Likely_benign. The variant received -6 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.

BS1

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.1800+21C>T		intron_variant	Intron 15 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.1800+21C>T	intron_variant	Intron 15 of 23	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.-928-733C>T	intron_variant	Intron 1 of 10			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.-340+1009C>T	intron_variant	Intron 1 of 10			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.-524+21C>T	intron_variant	Intron 2 of 11			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.-524+1009C>T	intron_variant	Intron 1 of 10			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.-437+1009C>T	intron_variant	Intron 1 of 10			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2236+2187C>T	intron_variant	Intron 17 of 25	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00135

AC:

337

AN:

249142

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00184

AC:

2673

AN:

1454882

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1319

AN XY:

724236

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33326

American (AMR)

AF:

0.00199

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.000126

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86100

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00223

AC:

2461

AN:

1105660

Other (OTH)

AF:

0.00176

AC:

106

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

121

242

363

484

605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00150

AC:

228

AN:

152246

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41546

American (AMR)

AF:

0.00281

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00223

AC:

152

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00137

Hom.:

Bravo

AF:

0.00156

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000070.3: c.1800+21C>T variant in CAPN3 is an intronic variant that does not occur in a splice region (+7/-21). The filtering allele frequency for this variant is 0.002152 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2461/1105660 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.01, which is less than the VCEP threshold of 0.05 (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4, BP7. -

not provided

Benign:1

Nov 05, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.4

(source)

DANN

Benign

0.51

PhyloP100

0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over