dbSNP rs28364396: CAPN3:c.380-27C>T (chr15-42386140-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000070.3(CAPN3):c.380-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,522,580 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 55 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 39 hom. )

Consequence

CAPN3
NM_000070.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.388

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 15-42386140-C-T is Benign according to our data. Variant chr15-42386140-C-T is described in ClinVar as Benign. ClinVar VariationId is 254872.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 = 0.0146 (2222/152258) while in subpopulation AFR AF = 0.0511 (2123/41536). AF 95% confidence interval is 0.0493. There are 55 homozygotes in GnomAd4. There are 1036 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 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	Effect	Exon Rank	Protein	UniProt
CAPN3	NM_000070.3	MANE Select	c.380-27C>T	intron	N/A	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.380-27C>T	intron	N/A	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.380-27C>T	intron	N/A	NP_775110.1	P20807-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.380-27C>T	intron	N/A	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.380-27C>T	intron	N/A	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.380-27C>T	intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2217

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0512

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

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:

0.000118

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00369

AC:

926

AN:

250832

AF XY:

0.00257

show subpopulations

Gnomad AFR exome

AF:

0.0517

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00141

AC:

1929

AN:

1370322

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

826

AN XY:

687168

show subpopulations

African (AFR)

AF:

0.0503

AC:

1596

AN:

31700

American (AMR)

AF:

0.00222

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25598

East Asian (EAS)

AF:

0.00

AC:

AN:

39232

South Asian (SAS)

AF:

0.0000947

AC:

AN:

84456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52720

Middle Eastern (MID)

AF:

0.000717

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

0.0000457

AC:

AN:

1028974

Other (OTH)

AF:

0.00304

AC:

175

AN:

57476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0146

AC:

2222

AN:

152258

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1036

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0511

AC:

2123

AN:

41536

American (AMR)

AF:

0.00458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68014

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00762

Hom.:

Bravo

AF:

0.0157

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

6.4

(source)

DANN

Benign

0.39

PhyloP100

-0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

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