15-42359808-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000070.3(CAPN3):c.3G>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.34

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000070.3 (CAPN3) was described as [Likely_pathogenic] in ClinVar as 556702
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42359808-G-T is Pathogenic according to our data. Variant chr15-42359808-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2032843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.3G>T	p.Met1?	start_lost	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.3G>T	p.Met1?	start_lost	1/23
CAPN3	NM_173087.2	c.3G>T	p.Met1?	start_lost	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.3G>T	p.Met1?	start_lost	1/24	1	NM_000070.3	P2
CAPN3	ENST00000357568.8	c.3G>T	p.Met1?	start_lost	1/23	1
CAPN3	ENST00000349748.8	c.3G>T	p.Met1?	start_lost	1/21	1
CAPN3	ENST00000318023.11	c.3G>T	p.Met1?	start_lost	1/23	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CAPN3 protein in which other variant(s) (p.Arg49Cys) have been determined to be pathogenic (PMID: 18055493, 18334579, 19285864, 19556129, 28403181). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 25135358). This sequence change affects the initiator methionine of the CAPN3 mRNA. The next in-frame methionine is located at codon 228. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.017	T;.;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-0.61	N;N;N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97, 0.99, 0.96	.;D;D;D
Vest4		0.94
MutPred		0.97		Loss of MoRF binding (P = 0.0839);Loss of MoRF binding (P = 0.0839);Loss of MoRF binding (P = 0.0839);Loss of MoRF binding (P = 0.0839);
MVP		0.94
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42652006;