rs1555422293

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000070.3(CAPN3):​c.1642del​(p.Arg548AlafsTer47) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.95
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 15-42402897-TC-T is Pathogenic according to our data. Variant chr15-42402897-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558200.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-42402897-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CAPN3NM_000070.3 linkuse as main transcriptc.1642del p.Arg548AlafsTer47 frameshift_variant 13/24 ENST00000397163.8
CAPN3NM_024344.2 linkuse as main transcriptc.1642del p.Arg548AlafsTer108 frameshift_variant 13/23
CAPN3NM_173087.2 linkuse as main transcriptc.1498del p.Arg500AlafsTer70 frameshift_variant 12/21
CAPN3NM_173088.2 linkuse as main transcriptc.106del p.Arg36AlafsTer47 frameshift_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CAPN3ENST00000397163.8 linkuse as main transcriptc.1642del p.Arg548AlafsTer47 frameshift_variant 13/241 NM_000070.3 P2P20807-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylMay 04, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555422293; hg19: chr15-42695095; API