rs28364489

Variant names:

• chr15-42402088-AC-A
• rs28364489
• NM_000070.3:c.1525-35delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000397163.8(CAPN3):​c.1525-35delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,613,784 control chromosomes in the GnomAD database, including 220 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (197 hom.)
• Consequence: CAPN3 ENST00000397163.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06
• 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 -16 ACMG points.

• BP6: Variant 15-42402088-AC-A is Benign according to our data. Variant chr15-42402088-AC-A is described in ClinVar as Benign. ClinVar VariationId is 254860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397163.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1525-35delC		intron	N/A	NP_000061.1
	CAPN3	NM_024344.2		c.1525-35delC		intron	N/A	NP_077320.1
	CAPN3	NM_173087.2		c.1381-35delC		intron	N/A	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1525-35delC		intron	N/A	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1525-35delC		intron	N/A	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1381-35delC		intron	N/A	ENSP00000183936.4

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152118 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0872

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00720 AC: 1809 AN: 251322 AF XY: 0.00657

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0897

Gnomad FIN exome AF: 0.000651

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00301 AC: 4405 AN: 1461548 Hom.: 197 Cov.: 32 AF XY: 0.00305 AC XY: 2220 AN XY: 727112

African (AFR) AF: 0.000269 AC: 9 AN: 33476

American (AMR) AF: 0.000358 AC: 16 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0915 AC: 3634 AN: 39698

South Asian (SAS) AF: 0.00233 AC: 201 AN: 86256

European-Finnish (FIN) AF: 0.000676 AC: 36 AN: 53236

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000220 AC: 245 AN: 1111870

Other (OTH) AF: 0.00436 AC: 263 AN: 60388

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152236 Hom.: 23 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74426

African (AFR) AF: 0.000505 AC: 21 AN: 41544

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0867 AC: 448 AN: 5170

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68002

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000545 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28364489; hg19: chr15-42694286;