rs1555420075

Positions:

• chr15-42384494-G-GAATCCCCGATTTA

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.322_334dup​(p.Ile112LysfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.46

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 15-42384494-G-GAATCCCCGATTTA is Pathogenic according to our data. Variant chr15-42384494-G-GAATCCCCGATTTA is described in ClinVar as [Pathogenic]. Clinvar id is 446980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.322_334dup	p.Ile112LysfsTer7	frameshift_variant	2/24	ENST00000397163.8
CAPN3	NM_024344.2	c.322_334dup	p.Ile112LysfsTer7	frameshift_variant	2/23
CAPN3	NM_173087.2	c.322_334dup	p.Ile112LysfsTer7	frameshift_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.322_334dup	p.Ile112LysfsTer7	frameshift_variant	2/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2019

Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 446980). This sequence change creates a premature translational stop signal (p.Ile112Lysfs*7) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555420075; hg19: chr15-42676692;