chr15-42390033-G-GGATA

Variant names:

• chr15-42390033-G-GGATA
• rs863224966
• NM_000070.3:c.883_886dupGATA

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.883_886dupGATA​(p.Asn296ArgfsTer2) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. 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, stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.25
• Publications: 0 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 15-42390033-G-GGATA is Pathogenic according to our data. Variant chr15-42390033-G-GGATA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3240990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.883_886dupGATA	p.Asn296ArgfsTer2	frameshift stop_gained	Exon 6 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.883_886dupGATA	p.Asn296ArgfsTer2	frameshift stop_gained	Exon 6 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.801+938_801+941dupGATA		intron	N/A	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.883_886dupGATA	p.Asn296ArgfsTer2	frameshift stop_gained	Exon 6 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.883_886dupGATA	p.Asn296ArgfsTer2	frameshift stop_gained	Exon 6 of 23	ENSP00000350181.3
	ENSG00000258461	ENST00000495723.1	TSL:2	n.*679_*682dupGATA		non_coding_transcript_exon	Exon 10 of 26	ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Mar 21, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs863224966; hg19: chr15-42682231;