rs398123147

Positions:

• chr15-42410651-G-GCAGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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]

ENSG00000258461 (HGNC:):

ACMG classification

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
CAPN3	NM_000070.3	c.2251_2254dupGTCA	p.Asn752fs	frameshift_variant	21/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2251_2254dupGTCA	p.Asn752fs	frameshift_variant	21/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.256_259dupGTCA	p.Asn87fs	frameshift_variant	8/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.256_259dupGTCA	p.Asn87fs	frameshift_variant	8/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.256_259dupGTCA	p.Asn87fs	frameshift_variant	9/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.256_259dupGTCA	p.Asn87fs	frameshift_variant	8/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.154_157dupGTCA	p.Asn53fs	frameshift_variant	8/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2687_*2690dupGTCA		non_coding_transcript_exon_variant	23/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2687_*2690dupGTCA		3_prime_UTR_variant	23/26	2		ENSP00000492063.1

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

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 04, 2013

- -

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: rs398123147; hg19: chr15-42702849;