rs1555421871

Positions:

• chr15-42399616-CG-C

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.1322delG​(p.Gly441fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000343 in 1,458,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.90

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 15-42399616-CG-C is Pathogenic according to our data. Variant chr15-42399616-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 281062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399616-CG-C is described in Lovd as [Pathogenic]. Variant chr15-42399616-CG-C is described in Lovd as [Pathogenic]. Variant chr15-42399616-CG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1322delG	p.Gly441fs	frameshift_variant	10/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1322delG	p.Gly441fs	frameshift_variant	10/23		NP_077320.1
CAPN3	NM_173087.2	c.1178delG	p.Gly393fs	frameshift_variant	9/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1322delG	p.Gly441fs	frameshift_variant	10/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1118delG		non_coding_transcript_exon_variant	14/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1118delG		3_prime_UTR_variant	14/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247520 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133934

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458896 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	This sequence change creates a premature translational stop signal (p.Gly441Valfs*22) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 281062). This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 15733273). This variant is present in population databases (no rsID available, gnomAD 0.0009%). -

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

Pathogenic, flagged submission

clinical testing

Baylor Genetics

Oct 12, 2023

- -

Cardiac arrhythmia;C0026850:Muscular dystrophy;C0151786:Muscle weakness;C0409338:Elbow flexion contracture;C1859523:Lower-limb joint contracture Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 24, 2014

- -

CAPN3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

The c.1322delG;p.(Gly441Valfs*22) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 26501342; PMID: 25135358; PMID: 17702496; PMID: 17236769) - PS4. This variant is not present in population databases (rs1555421871- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Gly441Valfs*22) was detected in trans with a pathogenic variant (PMID: 26501342; PMID: 25135358) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555421871; hg19: chr15-42691814;