ENST00000673743:c.-52G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000673743.1(CAPN3):c.-52G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,350,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CAPN3
ENST00000673743.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.22

Publications

0 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
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_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25755763).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000673743.1. 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.2041G>A	p.Val681Met	missense	Exon 18 of 24	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.2023G>A	p.Val675Met	missense	Exon 17 of 23	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.1765G>A	p.Val589Met	missense	Exon 15 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAPN3	ENST00000673743.1		c.-52G>A		5_prime_UTR_premature_start_codon_gain	Exon 5 of 11	ENSP00000500989.1	A0A669KAX6
CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2041G>A	p.Val681Met	missense	Exon 18 of 24	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.2023G>A	p.Val675Met	missense	Exon 17 of 23	ENSP00000350181.3	P20807-3

Frequencies

GnomAD3 genomes

AF:

0.0000762

AC:

AN:

131208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000268

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000790

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251162

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1219574

Hom.:

Cov.:

AF XY:

0.0000197

AC XY:

AN XY:

607754

show subpopulations

African (AFR)

AF:

0.0000746

AC:

AN:

26810

American (AMR)

AF:

0.0000510

AC:

AN:

39206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18712

East Asian (EAS)

AF:

0.0000451

AC:

AN:

22194

South Asian (SAS)

AF:

0.00

AC:

AN:

83234

European-Finnish (FIN)

AF:

0.0000509

AC:

AN:

39278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4646

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

939390

Other (OTH)

AF:

0.00

AC:

AN:

46104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

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:

0.0000762

AC:

AN:

131268

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

62192

show subpopulations

African (AFR)

AF:

0.000112

AC:

AN:

35698

American (AMR)

AF:

0.00

AC:

AN:

11570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3284

East Asian (EAS)

AF:

0.00

AC:

AN:

3782

South Asian (SAS)

AF:

0.000267

AC:

AN:

3746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000790

AC:

AN:

63276

Other (OTH)

AF:

0.00

AC:

AN:

1856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

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:

0.0000389

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.076

MetaRNN

Benign

0.26

MetaSVM

Uncertain

0.019

MutationAssessor

Benign

1.7

PhyloP100

1.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.38

Sift

Benign

0.053

Sift4G

Benign

0.24

Polyphen

0.99

Vest4

0.54

MVP

0.91

MPC

0.50

ClinPred

0.44

GERP RS

4.8

Varity_R

0.26

gMVP

0.30

Mutation Taster

=65/35

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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