rs398123147

Variant summary

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

The NM_000070.3(CAPN3):​c.2251_2254dupGTCA​(p.Asn752fs) 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: 31)

Consequence

CAPN3
NM_000070.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91
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 15-42410651-G-GCAGT is Pathogenic according to our data. Variant chr15-42410651-G-GCAGT is described in ClinVar as [Pathogenic]. Clinvar id is 92412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAPN3NM_000070.3 linkc.2251_2254dupGTCA p.Asn752fs frameshift_variant 21/24 ENST00000397163.8 NP_000061.1 P20807-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAPN3ENST00000397163.8 linkc.2251_2254dupGTCA p.Asn752fs frameshift_variant 21/241 NM_000070.3 ENSP00000380349.3 P20807-1
CAPN3ENST00000673886.1 linkc.256_259dupGTCA p.Asn87fs frameshift_variant 8/11 ENSP00000501155.1 P20807-5
CAPN3ENST00000673928.1 linkc.256_259dupGTCA p.Asn87fs frameshift_variant 8/11 ENSP00000501099.1 P20807-5
CAPN3ENST00000674146.1 linkc.256_259dupGTCA p.Asn87fs frameshift_variant 9/12 ENSP00000501175.1 P20807-5
CAPN3ENST00000674149.1 linkc.256_259dupGTCA p.Asn87fs frameshift_variant 8/11 ENSP00000501112.1 P20807-5
CAPN3ENST00000673743.1 linkc.154_157dupGTCA p.Asn53fs frameshift_variant 8/11 ENSP00000500989.1 A0A669KAX6
ENSG00000258461ENST00000495723.1 linkn.*2687_*2690dupGTCA non_coding_transcript_exon_variant 23/262 ENSP00000492063.1 A0A1W2PQD3
ENSG00000258461ENST00000495723.1 linkn.*2687_*2690dupGTCA 3_prime_UTR_variant 23/262 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 04, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs398123147; hg19: chr15-42702849; API