Variant 15-42360037-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The ENST00000397163.8(CAPN3):c.232C>T(p.Pro78Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P78T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAPN3
ENST00000397163.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.12

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000397163.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42360037-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAPN3	NM_000070.3 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/24	1	NM_000070.3	ENSP00000380349	P2	P20807-1
CAPN3	ENST00000357568.8 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/23	1		ENSP00000350181		P20807-3
CAPN3	ENST00000349748.8 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/21	1		ENSP00000183936		P20807-2
CAPN3	ENST00000318023.11 linkuse as main transcript	c.232C>T	p.Pro78Ser	missense_variant	1/23	5		ENSP00000326281	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249514

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135008

show subpopulations

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:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.5

.;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.52

Sift

Benign

0.049

D;D;D;D

Sift4G

Uncertain

0.037

D;T;D;T

Polyphen

0.59, 0.45, 0.64

.;P;B;P

Vest4

0.54

MutPred

0.70

Gain of phosphorylation at P78 (P = 0.0635);Gain of phosphorylation at P78 (P = 0.0635);Gain of phosphorylation at P78 (P = 0.0635);Gain of phosphorylation at P78 (P = 0.0635);

MVP

0.95

MPC

0.39

ClinPred

0.94

GERP RS

6.0

Varity_R

0.55

gMVP

0.74

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over