rs398123147

Variant names:

• chr15-42410651-G-GCAGT
• rs398123147
• NM_000070.3:c.2251_2254dupGTCA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000070.3(CAPN3):​c.2251_2254dupGTCA​(p.Asn752SerfsTer14) 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 (★). Synonymous variant affecting the same amino acid position (i.e. N752N) has been classified as Likely benign. 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
• 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 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 VariationId is 92412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2251_2254dupGTCA	p.Asn752SerfsTer14	frameshift_variant	Exon 21 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2251_2254dupGTCA	p.Asn752SerfsTer14	frameshift_variant	Exon 21 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.256_259dupGTCA	p.Asn87SerfsTer14	frameshift_variant	Exon 8 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.256_259dupGTCA	p.Asn87SerfsTer14	frameshift_variant	Exon 8 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.256_259dupGTCA	p.Asn87SerfsTer14	frameshift_variant	Exon 9 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.256_259dupGTCA	p.Asn87SerfsTer14	frameshift_variant	Exon 8 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.154_157dupGTCA	p.Asn53SerfsTer14	frameshift_variant	Exon 8 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2687_*2690dupGTCA		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2687_*2690dupGTCA		3_prime_UTR_variant	Exon 23 of 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

Oct 04, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
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: rs398123147; hg19: chr15-42702849;