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 ENST00000397163.8(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
ENST00000397163.8 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 VariationId is 553754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397163.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAPN3	NM_000070.3	MANE Select	c.2050+1G>A	splice_donor intron	N/A	NP_000061.1
CAPN3	NM_024344.2		c.2032+1G>A	splice_donor intron	N/A	NP_077320.1
CAPN3	NM_173087.2		c.1774+1G>A	splice_donor intron	N/A	NP_775110.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2050+1G>A	splice_donor intron	N/A	ENSP00000380349.3
CAPN3	ENST00000357568.8	TSL:1	c.2032+1G>A	splice_donor intron	N/A	ENSP00000350181.3
CAPN3	ENST00000349748.8	TSL:1	c.1774+1G>A	splice_donor intron	N/A	ENSP00000183936.4

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

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:

0.00000725

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

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2A (4)

Autosomal recessive limb-girdle muscular dystrophy (1)

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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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

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over