15-42399500-A-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM5PP5_Very_StrongBP4

The NM_000070.3(CAPN3):c.1202A>T(p.Tyr401Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y401C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.36

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):

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: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health
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: Likely_pathogenic. The variant received 9 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42399500-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 553468.

PP5

Variant 15-42399500-A-T is Pathogenic according to our data. Variant chr15-42399500-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 965033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18262953). . Strength limited to SUPPORTING due to the PP5.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
CAPN3	NM_000070.3	MANE Select	c.1202A>T	p.Tyr401Phe	missense	Exon 10 of 24	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.1202A>T	p.Tyr401Phe	missense	Exon 10 of 23	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.1058A>T	p.Tyr353Phe	missense	Exon 9 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1202A>T	p.Tyr401Phe	missense	Exon 10 of 24	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.1202A>T	p.Tyr401Phe	missense	Exon 10 of 23	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.1058A>T	p.Tyr353Phe	missense	Exon 9 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251462

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1460926

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111168

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

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

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0076

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.069

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.017

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.67

MutationAssessor

Benign

-0.28

PhyloP100

5.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.94

REVEL

Uncertain

0.31

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.35

MutPred

0.69

Gain of sheet (P = 0.1451)

MVP

0.81

MPC

0.13

ClinPred

0.36

GERP RS

5.2

Varity_R

0.25

gMVP

0.67

Mutation Taster

=75/25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over