rs886042573

chr15-42402999-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000070.3(CAPN3):c.1743_1744del(p.Glu582GlyfsTer3) variant causes a frameshift, splice region change. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.73

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-42402999-CTG-C is Pathogenic according to our data. Variant chr15-42402999-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 283179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42402999-CTG-C is described in Lovd as [Pathogenic]. Variant chr15-42402999-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1743_1744del	p.Glu582GlyfsTer3	frameshift_variant, splice_region_variant	13/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1743_1744del	p.Glu582GlyfsTer3	frameshift_variant, splice_region_variant	13/23
CAPN3	NM_173087.2	c.1599_1600del	p.Glu534GlyfsTer3	frameshift_variant, splice_region_variant	12/21
CAPN3	NM_173088.2	c.207_208del	p.Glu70GlyfsTer3	frameshift_variant, splice_region_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1743_1744del	p.Glu582GlyfsTer3	frameshift_variant, splice_region_variant	13/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 30, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 10330340). ClinVar contains an entry for this variant (Variation ID: 283179). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu582Glyfs*3) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 29, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 29, 2018

- -

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: rs886042573; hg19: chr15-42695197;