rs28364489

chr15-42402088-AC-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000070.3(CAPN3):c.1525-35del 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 NM_000070.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1525-35del		intron_variant		ENST00000397163.8
CAPN3	NM_024344.2	c.1525-35del		intron_variant
CAPN3	NM_173087.2	c.1381-35del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1525-35del		intron_variant		1	NM_000070.3	P2

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

GnomAD3 exomes AF: 0.00720 AC: 1809 AN: 251322 Hom.: 68 AF XY: 0.00657 AC XY: 893 AN XY: 135844

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 SAS exome AF: 0.00222

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

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0915

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.000676

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00436

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

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0867

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000545 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs28364489; hg19: chr15-42694286;