15-42359808-G-T

Variant names:

• chr15-42359808-G-T
• NM_000070.3:c.3G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 152 pathogenic variants. Next in-frame start position is after 228 codons. Genomic position: 42388977. Lost 0.277 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.3G>T	p.Met1?	start_lost	Exon 1 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.3G>T	p.Met1?	start_lost	Exon 1 of 23		NP_077320.1
CAPN3	NM_173087.2	c.3G>T	p.Met1?	start_lost	Exon 1 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.3G>T	p.Met1?	start_lost	Exon 1 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5355G>T		intron_variant	Intron 5 of 25	2		ENSP00000492063.1

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

Oct 03, 2022

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 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 variant is not present in population databases (gnomAD no frequency). 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
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;