rs398123150

Variant names:

• chr15-42390004-G-GAGTTGATTGC
• rs398123150
• NM_000070.3:c.855_864dupGTTGATTGCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.855_864dupGTTGATTGCA​(p.Arg289ValfsTer11) variant causes a frameshift change. 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: 5.52
• Publications: 1 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 15-42390004-G-GAGTTGATTGC is Pathogenic according to our data. Variant chr15-42390004-G-GAGTTGATTGC is described in ClinVar as Pathogenic. ClinVar VariationId is 92421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.855_864dupGTTGATTGCA	p.Arg289ValfsTer11	frameshift_variant	Exon 6 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.855_864dupGTTGATTGCA	p.Arg289ValfsTer11	frameshift_variant	Exon 6 of 23		NP_077320.1
CAPN3	NM_173087.2	c.801+910_801+919dupGTTGATTGCA		intron_variant	Intron 5 of 20		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.855_864dupGTTGATTGCA	p.Arg289ValfsTer11	frameshift_variant	Exon 6 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*651_*660dupGTTGATTGCA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*651_*660dupGTTGATTGCA		3_prime_UTR_variant	Exon 10 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 92421). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg289Valfs*11) 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

Apr 30, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs398123150; hg19: chr15-42682202;