rs886042478

chr15-42360050-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP3 PP5_Very_Strong

The NM_000070.3(CAPN3):c.245C>T(p.Pro82Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,192 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P82P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.81

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 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000070.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807
• PP5: Variant 15-42360050-C-T is Pathogenic according to our data. Variant chr15-42360050-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42360050-C-T is described in Lovd as [Pathogenic]. Variant chr15-42360050-C-T is described in Lovd as [Pathogenic]. Variant chr15-42360050-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42360050-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.245C>T	p.Pro82Leu	missense_variant	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.245C>T	p.Pro82Leu	missense_variant	1/23
CAPN3	NM_173087.2	c.245C>T	p.Pro82Leu	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.245C>T	p.Pro82Leu	missense_variant	1/24	1	NM_000070.3	P2
CAPN3	ENST00000357568.8	c.245C>T	p.Pro82Leu	missense_variant	1/23	1
CAPN3	ENST00000349748.8	c.245C>T	p.Pro82Leu	missense_variant	1/21	1
CAPN3	ENST00000318023.11	c.245C>T	p.Pro82Leu	missense_variant	1/23	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249310 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134926

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12461690, 12890817, 15689361, 16100770, 16141003, 15221789, 16372320, 15351423, 20635405, 14981715, 27023906, 17157502, 31980526, 31862442, 27447704, 26886200, 29970176, 35157181, 25135358, 31555977, 35894554, 36385624) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 04, 2016	- -

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

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the CAPN3 protein (p.Pro82Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 12461690, 12890817, 15221789, 15351423, 16100770, 16141003, 16372320, 17157502, 20635405, 25135358, 26886200, 27447704). ClinVar contains an entry for this variant (Variation ID: 282783). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.89, 0.99, 0.95	.;P;D;P
Vest4		0.82
MVP		0.98
MPC		0.36
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.62
gMVP		0.84

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: rs886042478; hg19: chr15-42652248;