Variant chr15-42359807-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.12

Variant links:

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]

CAPN3 links:

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ACMG classification

Classification made for transcript

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
CAPN3	NM_000070.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/23
CAPN3	NM_173087.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/24	1	NM_000070.3	P2	P20807-1
CAPN3	ENST00000357568.8 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/23	1			P20807-3
CAPN3	ENST00000349748.8 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/21	1			P20807-2
CAPN3	ENST00000318023.11 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/23	5		A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726908

show subpopulations

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.;.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

0.73

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over