rs886042573

Positions:

• chr15-42402999-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.1743_1744del​(p.Glu582GlyfsTer3) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• 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	Protein	UniProt
CAPN3	NM_000070.3	c.1743_1744del	p.Glu582GlyfsTer3	frameshift_variant, splice_region_variant	13/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1743_1744del	p.Glu582GlyfsTer3	frameshift_variant, splice_region_variant	13/23		NP_077320.1
CAPN3	NM_173087.2	c.1599_1600del	p.Glu534GlyfsTer3	frameshift_variant, splice_region_variant	12/21		NP_775110.1
CAPN3	NM_173088.2	c.207_208del	p.Glu70GlyfsTer3	frameshift_variant, splice_region_variant	2/13		NP_775111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1743_1744del	p.Glu582GlyfsTer3	frameshift_variant, splice_region_variant	13/24	1	NM_000070.3	ENSP00000380349	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

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). -

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;