chr15-42410606-GAC-G

Position:

• chr15-42410606-GAC-G

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.2207_2208delCA​(p.Thr736fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.32

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 15-42410606-GAC-G is Pathogenic according to our data. Variant chr15-42410606-GAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410606-GAC-G is described in Lovd as [Pathogenic]. Variant chr15-42410606-GAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2207_2208delCA	p.Thr736fs	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.2207_2208delCA	p.Thr736fs	frameshift_variant	21/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.212_213delCA	p.Thr71fs	frameshift_variant	8/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.212_213delCA	p.Thr71fs	frameshift_variant	8/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.212_213delCA	p.Thr71fs	frameshift_variant	9/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.212_213delCA	p.Thr71fs	frameshift_variant	8/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.110_111delCA	p.Thr37fs	frameshift_variant	8/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2643_*2644delCA		non_coding_transcript_exon_variant	23/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2643_*2644delCA		3_prime_UTR_variant	23/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 128569). This variant is also known as 2204_2205del, T736fs+2X27. This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 16141003). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr736Argfs*28) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 02, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 25, 2018	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 18, 2023

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2022

Identified in patients with limb-girdle muscular dystrophy, however, no specific clinical or segregation information was provided (Piluso et al., 2005; Zhong et al., 2021); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16141003, 32994280) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780289; hg19: chr15-42702804;