NM_000070.3:c.498+32A>C

Variant names:

• chr15-42386317-A-C
• rs28364398
• NM_000070.3:c.498+32A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000070.3(CAPN3):​c.498+32A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,469,384 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (70 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.931
• Publications: 2 publications found

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):

• 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-42386317-A-C is Benign according to our data. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386317-A-C is described in CliVar as Benign. Clinvar id is 254873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.498+32A>C		intron_variant	Intron 3 of 23	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.498+32A>C		intron_variant	Intron 3 of 22		NP_077320.1
CAPN3	NM_173087.2	c.498+32A>C		intron_variant	Intron 3 of 20		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.498+32A>C		intron_variant	Intron 3 of 23	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*294+32A>C		intron_variant	Intron 7 of 25	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2696 AN: 152148 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00480 AC: 1205 AN: 250882 AF XY: 0.00356

Gnomad AFR exome AF: 0.0601

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00214 AC: 2821 AN: 1317118 Hom.: 70 Cov.: 20 AF XY: 0.00184 AC XY: 1218 AN XY: 663148

African (AFR) AF: 0.0625 AC: 1920 AN: 30698

American (AMR) AF: 0.00445 AC: 198 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 31 AN: 25300

East Asian (EAS) AF: 0.00 AC: 0 AN: 39046

South Asian (SAS) AF: 0.000275 AC: 23 AN: 83510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.00452 AC: 25 AN: 5528

European-Non Finnish (NFE) AF: 0.000354 AC: 347 AN: 979930

Other (OTH) AF: 0.00499 AC: 277 AN: 55566

GnomAD4 genome AF: 0.0177 AC: 2698 AN: 152266 Hom.: 73 Cov.: 32 AF XY: 0.0168 AC XY: 1249 AN XY: 74456

African (AFR) AF: 0.0605 AC: 2514 AN: 41552

American (AMR) AF: 0.00706 AC: 108 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68010

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0189 Hom.: 27

Bravo AF: 0.0198

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.46
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs28364398; hg19: chr15-42678515;