rs28364538

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000070.3(CAPN3):c.2380+12delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,592,214 control chromosomes in the GnomAD database, including 3,022 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 223 hom., cov: 31)

Exomes 𝑓: 0.060 ( 2799 hom. )

Consequence

CAPN3
NM_000070.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.657

Publications

10 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: Benign. The variant received -16 ACMG points.

BP6

Variant 15-42411011-GA-G is Benign according to our data. Variant chr15-42411011-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2380+12delA		intron_variant	Intron 22 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.2380+12delA	intron_variant	Intron 22 of 23	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.385+12delA	intron_variant	Intron 9 of 10			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.385+12delA	intron_variant	Intron 9 of 10			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.385+12delA	intron_variant	Intron 10 of 11			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.385+12delA	intron_variant	Intron 9 of 10			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.283+12delA	intron_variant	Intron 9 of 10			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2816+12delA	intron_variant	Intron 24 of 25	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

6877

AN:

152220

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.0648

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0701

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0662

Gnomad OTH

AF:

0.0516

GnomAD2 exomes

AF:

0.0461

AC:

11569

AN:

251222

AF XY:

0.0465

show subpopulations

Gnomad AFR exome

AF:

0.00966

Gnomad AMR exome

AF:

0.0291

Gnomad ASJ exome

AF:

0.0637

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0617

Gnomad NFE exome

AF:

0.0650

Gnomad OTH exome

AF:

0.0524

GnomAD4 exome

AF:

0.0596

AC:

85854

AN:

1439876

Hom.:

2799

Cov.:

AF XY:

0.0588

AC XY:

42213

AN XY:

717780

show subpopulations

African (AFR)

AF:

0.00794

AC:

262

AN:

32996

American (AMR)

AF:

0.0308

AC:

1376

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0653

AC:

1698

AN:

25986

East Asian (EAS)

AF:

0.000177

AC:

AN:

39554

South Asian (SAS)

AF:

0.0252

AC:

2165

AN:

85828

European-Finnish (FIN)

AF:

0.0616

AC:

3285

AN:

53368

Middle Eastern (MID)

AF:

0.0342

AC:

196

AN:

5734

European-Non Finnish (NFE)

AF:

0.0673

AC:

73457

AN:

1092046

Other (OTH)

AF:

0.0571

AC:

3408

AN:

59666

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

4423

8846

13270

17693

22116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2624

5248

7872

10496

13120

<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:

0.0451

AC:

6873

AN:

152338

Hom.:

223

Cov.:

AF XY:

0.0439

AC XY:

3268

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0118

AC:

491

AN:

41588

American (AMR)

AF:

0.0388

AC:

593

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0648

AC:

225

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0257

AC:

124

AN:

4832

European-Finnish (FIN)

AF:

0.0701

AC:

744

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0662

AC:

4503

AN:

68022

Other (OTH)

AF:

0.0510

AC:

108

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

340

680

1019

1359

1699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0413

Hom.:

Bravo

AF:

0.0414

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:4

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.66

Mutation Taster

=95/5

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over