rs28364538

Positions:

• chr15-42411011-GA-G

Variant summary

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

The NM_000070.3(CAPN3):​c.2380+12delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,592,214 control chromosomes in the GnomAD database, including 3,022 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (223 hom., cov: 31)
  • Exomes 𝑓: 0.060 (2799 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.657

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 15-42411011-GA-G is Benign according to our data. Variant chr15-42411011-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 166792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42411011-GA-G is described in Lovd as [Benign]. Variant chr15-42411011-GA-G is described in Lovd as [Likely_benign]. Variant chr15-42411011-GA-G is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2380+12delA		intron_variant		ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2380+12delA		intron_variant		1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.385+12delA		intron_variant				ENSP00000501155.1
CAPN3	ENST00000673928.1	c.385+12delA		intron_variant				ENSP00000501099.1
CAPN3	ENST00000674146.1	c.385+12delA		intron_variant				ENSP00000501175.1
CAPN3	ENST00000674149.1	c.385+12delA		intron_variant				ENSP00000501112.1
CAPN3	ENST00000673743.1	c.283+12delA		intron_variant				ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2816+12delA		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6877 AN: 152220 Hom.: 224 Cov.: 31

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0516

GnomAD3 exomes AF: 0.0461 AC: 11569 AN: 251222 Hom.: 359 AF XY: 0.0465 AC XY: 6311 AN XY: 135762

Gnomad AFR exome AF: 0.00966

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.0617

Gnomad NFE exome AF: 0.0650

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0596 AC: 85854 AN: 1439876 Hom.: 2799 Cov.: 26 AF XY: 0.0588 AC XY: 42213 AN XY: 717780

Gnomad4 AFR exome AF: 0.00794

Gnomad4 AMR exome AF: 0.0308

Gnomad4 ASJ exome AF: 0.0653

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.0616

Gnomad4 NFE exome AF: 0.0673

Gnomad4 OTH exome AF: 0.0571

GnomAD4 genome AF: 0.0451 AC: 6873 AN: 152338 Hom.: 223 Cov.: 31 AF XY: 0.0439 AC XY: 3268 AN XY: 74476

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.0701

Gnomad4 NFE AF: 0.0662

Gnomad4 OTH AF: 0.0510

Alfa AF: 0.0413 Hom.: 43

Bravo AF: 0.0414

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2014	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs28364538; hg19: chr15-42703209;