15-42359807-T-C

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.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,150 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAPN3 NM_000070.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.12

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 [Pathogenic] in ClinVar as 2032843
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42359807-T-C is Pathogenic according to our data. Variant chr15-42359807-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556702.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.2T>C	p.Met1?	start_lost	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.2T>C	p.Met1?	start_lost	1/23
CAPN3	NM_173087.2	c.2T>C	p.Met1?	start_lost	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2T>C	p.Met1?	start_lost	1/24	1	NM_000070.3	P2
CAPN3	ENST00000357568.8	c.2T>C	p.Met1?	start_lost	1/23	1
CAPN3	ENST00000349748.8	c.2T>C	p.Met1?	start_lost	1/21	1
CAPN3	ENST00000318023.11	c.2T>C	p.Met1?	start_lost	1/23	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726908

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 13, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-0.95	N;N;N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99, 0.99, 0.98	.;D;D;D
Vest4		0.74
MutPred		0.97		Gain of glycosylation at M1 (P = 0.0058);Gain of glycosylation at M1 (P = 0.0058);Gain of glycosylation at M1 (P = 0.0058);Gain of glycosylation at M1 (P = 0.0058);
MVP		0.96
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.75
gMVP		0.80

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: rs1555417257; hg19: chr15-42652005;