rs768374736

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000070.3(CAPN3):c.2050+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000072 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000039 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 10.0

Publications

4 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 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 29, new splice context is: gggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 15-42409845-G-A is Pathogenic according to our data. Variant chr15-42409845-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 553754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2050+1G>A		splice_donor_variant, intron_variant	Intron 18 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.2050+1G>A	splice_donor_variant, intron_variant	Intron 18 of 23	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.55+1G>A	splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.55+1G>A	splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.55+1G>A	splice_donor_variant, intron_variant	Intron 6 of 11			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.55+1G>A	splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.-43+1G>A	splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2486+1G>A	splice_donor_variant, intron_variant	Intron 20 of 25	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00000725

AC:

AN:

137946

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:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251028

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000393

AC:

AN:

1272654

Hom.:

Cov.:

AF XY:

0.00000314

AC XY:

AN XY:

636152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28688

American (AMR)

AF:

0.00

AC:

AN:

41826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21680

East Asian (EAS)

AF:

0.0000647

AC:

AN:

30920

South Asian (SAS)

AF:

0.00

AC:

AN:

83344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5040

European-Non Finnish (NFE)

AF:

0.00000312

AC:

AN:

961760

Other (OTH)

AF:

0.00

AC:

AN:

50922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000725

AC:

AN:

137946

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

66056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37622

American (AMR)

AF:

0.00

AC:

AN:

13260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3328

East Asian (EAS)

AF:

0.00

AC:

AN:

4110

South Asian (SAS)

AF:

0.00

AC:

AN:

3898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64610

Other (OTH)

AF:

0.00

AC:

AN:

1910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000172

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:4

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 18 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 (rs768374736, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with limb-girdle muscular dystrophy (PMID: 11525884, 26632398, 26677118). ClinVar contains an entry for this variant (Variation ID: 553754). 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. -

May 10, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Sep 06, 2017

Counsyl

Significance: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. -

Aug 03, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant lies in the essential splice donor site, in intron 18 of the CAPN3 gene. In silico splice prediction tools (ASSP and NNSPLICE) suggest that this variant might affect splicing due to the loss of constitutive splice site and introduction of a new splice site, which in turn might lead to a frameshift and consequent premature termination of the protein; this will likely result in loss-of-function.It was previously reported in the compound heterozygous state in individuals affected with limb-girdle muscular dystrophy [PMID: 11525884, 26632398, 26677118]. -

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

Pathogenic:1

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Mar 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CAPN3 c.2050+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251028 control chromosomes. c.2050+1G>A has been reported in the literature in at-least two individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Chae_2001). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 11525884). ClinVar contains an entry for this variant (Variation ID: 553754). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Aug 02, 2022

Revvity Omics, Revvity

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

0.47

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

PhyloP100

GERP RS

4.8

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)

0.95

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: -26

DS_DL_spliceai

0.95

Position offset: -1

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.

rs768374736

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