Genetic Variant CAPN3:p.Thr184Met (chr15-42387805-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1PM5PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000070.3(CAPN3):c.551C>T(p.Thr184Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,142 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T184A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0094 ( 26 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 17 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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):

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: Benign. The variant received -15 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42387804-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 662930.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.012169331).

BP6

Variant 15-42387805-C-T is Benign according to our data. Variant chr15-42387805-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00938 (1428/152276) while in subpopulation AFR AF = 0.0332 (1380/41550). AF 95% confidence interval is 0.0318. There are 26 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AD,AR gene

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.551C>T	p.Thr184Met	missense	Exon 4 of 24	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.551C>T	p.Thr184Met	missense	Exon 4 of 23	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.551C>T	p.Thr184Met	missense	Exon 4 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.551C>T	p.Thr184Met	missense	Exon 4 of 24	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.551C>T	p.Thr184Met	missense	Exon 4 of 23	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.551C>T	p.Thr184Met	missense	Exon 4 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.00937

AC:

1425

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0332

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00242

AC:

608

AN:

251442

AF XY:

0.00163

show subpopulations

Gnomad AFR exome

AF:

0.0347

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000870

AC:

1272

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

557

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0334

AC:

1117

AN:

33480

American (AMR)

AF:

0.000984

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111986

Other (OTH)

AF:

0.00157

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

174

261

348

435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00938

AC:

1428

AN:

152276

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

631

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0332

AC:

1380

AN:

41550

American (AMR)

AF:

0.00209

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00334

Hom.:

Bravo

AF:

0.0107

ESP6500AA

AF:

0.0365

AC:

161

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00310

AC:

376

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Autosomal recessive limb-girdle muscular dystrophy type 2A (3)

not provided (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.7

PhyloP100

7.9

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.87

Sift

Uncertain

0.011

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.86

MVP

0.98

MPC

0.64

ClinPred

0.031

GERP RS

5.9

Varity_R

0.40

gMVP

0.83

Mutation Taster

=57/43

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