chr15-42389022-GATG-AT

Variant names:

• chr15-42389022-GATG-AT
• rs1555420642
• NM_000070.3:c.727_730delGATGinsAT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.727_730delGATGinsAT​(p.Asp243IlefsTer3) variant causes a frameshift, missense change. 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, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.19

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 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 15-42389022-GATG-AT is Pathogenic according to our data. Variant chr15-42389022-GATG-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536516.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.727_730delGATGinsAT	p.Asp243IlefsTer3	frameshift_variant, missense_variant	Exon 5 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.727_730delGATGinsAT	p.Asp243IlefsTer3	frameshift_variant, missense_variant	Exon 5 of 23		NP_077320.1
CAPN3	NM_173087.2	c.727_730delGATGinsAT	p.Asp243IlefsTer3	frameshift_variant, missense_variant	Exon 5 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.727_730delGATGinsAT	p.Asp243IlefsTer3	frameshift_variant, missense_variant	Exon 5 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*523_*526delGATGinsAT		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*523_*526delGATGinsAT		3_prime_UTR_variant	Exon 9 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/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 23, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1

May 30, 2023

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. This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Asp243Ilefs*3) 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). -

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: rs1555420642; hg19: chr15-42681220;