dbSNP rs28364467: CAPN3:c.1116-5A>G (chr15-42396795-A-G) – 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.1116-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,611,658 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene CAPN3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.011 ( 32 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 26 hom. )

Consequence

CAPN3
NM_000070.3 splice_region, intron

Scores

Splicing: ADA: 0.00002554

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.652

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

Specifications for CAPN3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 15-42396795-A-G is Benign according to our data. Variant chr15-42396795-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166788.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 = 0.0105 (1600/151852) while in subpopulation AFR AF = 0.0372 (1541/41374). AF 95% confidence interval is 0.0357. There are 32 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AD,AR,SD 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.1116-5A>G	splice_region intron	N/A	NP_000061.1	P20807-1
CAPN3	NM_024344.2		c.1116-5A>G	splice_region intron	N/A	NP_077320.1	P20807-3
CAPN3	NM_173087.2		c.972-5A>G	splice_region 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.1116-5A>G	splice_region intron	N/A	ENSP00000380349.3	P20807-1
CAPN3	ENST00000357568.8	TSL:1	c.1116-5A>G	splice_region intron	N/A	ENSP00000350181.3	P20807-3
CAPN3	ENST00000349748.8	TSL:1	c.972-5A>G	splice_region intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1594

AN:

151734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00268

AC:

674

AN:

251442

AF XY:

0.00202

show subpopulations

Gnomad AFR exome

AF:

0.0388

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00105

AC:

1540

AN:

1459806

Hom.:

Cov.:

AF XY:

0.000917

AC XY:

666

AN XY:

726372

show subpopulations

African (AFR)

AF:

0.0393

AC:

1315

AN:

33426

American (AMR)

AF:

0.00105

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000162

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1110146

Other (OTH)

AF:

0.00210

AC:

127

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0105

AC:

1600

AN:

151852

Hom.:

Cov.:

AF XY:

0.00973

AC XY:

722

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.0372

AC:

1541

AN:

41374

American (AMR)

AF:

0.00223

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000416

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67934

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

158

236

315

394

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:

0.00363

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

4.4

(source)

DANN

Benign

0.57

PhyloP100

0.65

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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