15-42384501-C-T

Position:

• chr15-42384501-C-T

Variant summary

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

The ENST00000397163.8(CAPN3):​c.328C>T​(p.Arg110Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 ENST00000397163.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.72

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]

LOC105370794 (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 15-42384501-C-T is Pathogenic according to our data. Variant chr15-42384501-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42384501-C-T is described in Lovd as [Pathogenic]. Variant chr15-42384501-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.328C>T	p.Arg110Ter	stop_gained	2/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.328C>T	p.Arg110Ter	stop_gained	2/23		NP_077320.1
CAPN3	NM_173087.2	c.328C>T	p.Arg110Ter	stop_gained	2/21		NP_775110.1
LOC105370794	XR_932178.3			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.328C>T	p.Arg110Ter	stop_gained	2/24	1	NM_000070.3	ENSP00000380349	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461486 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727090

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 21, 2023	ClinVar contains an entry for this variant (Variation ID: 17615). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive CAPN3-related conditions (PMID: 7720071, 16542520, 30028523). This variant is present in population databases (rs121434545, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg110*) 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, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 07, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017615). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Arg110Ter variant in CAPN3 was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD increases the likelihood that the p.Arg110Ter variant is pathogenic. This variant has been identified in 0.0008955% (1/111670) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434545). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 110, which is predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of another pathogenic variant in one individual with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015). -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.328C>T;p.(Arg110*) variant creates a premature translational stop signal in the CAPN3 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:17615; PMID: 16141003; 7720071; 16542520; 25135358; 30028523; 31931849) - PS4. The variant is present at low allele frequencies population databases (rs121434545– gnomAD 0.0006574%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg110*) was detected in trans with a pathogenic variant (PMID: 26677118; 18854869) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, flagged submission	clinical testing	Baylor Genetics	Mar 04, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.88
GERP RS		2.2

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: rs121434545; hg19: chr15-42676699; COSMIC: COSV58826545;