dbSNP rs140425651: CAPN3:p.Gly691Arg (chr15-42409951-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP3BP4_StrongBP6

The NM_000070.3(CAPN3):c.2071G>A(p.Gly691Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,612,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G691G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 8.11

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: 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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000070.3

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, FATHMM_MKL, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.06506458).

BP6

Variant 15-42409951-G-A is Benign according to our data. Variant chr15-42409951-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281011.

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.2071G>A	p.Gly691Arg	missense	Exon 19 of 24	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.2053G>A	p.Gly685Arg	missense	Exon 18 of 23	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.1795G>A	p.Gly599Arg	missense	Exon 16 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.2071G>A	p.Gly691Arg	missense	Exon 19 of 24	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.2053G>A	p.Gly685Arg	missense	Exon 18 of 23	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.1795G>A	p.Gly599Arg	missense	Exon 16 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00309

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

251388

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00152

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000760

AC:

111

AN:

1460174

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

726338

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000731

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000225

AC:

AN:

4438

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111910

Other (OTH)

AF:

0.000681

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00290

AC:

AN:

5170

South Asian (SAS)

AF:

0.000416

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000517

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.083

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.065

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.4

PhyloP100

8.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.92

Sift

Uncertain

0.022

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.88

MutPred

0.61

Gain of MoRF binding (P = 0.0314)

MVP

1.0

MPC

0.62

ClinPred

0.086

GERP RS

4.8

Varity_R

0.55

gMVP

0.75

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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