rs376107921

chr15-42399617-G-Achr15-42399617-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000070.3(CAPN3):c.1319G>A(p.Arg440Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,611,116 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.90

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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000070.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42399616-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 283991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 15-42399617-G-A is Pathogenic according to our data. Variant chr15-42399617-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399617-G-A is described in Lovd as [Pathogenic]. Variant chr15-42399617-G-A is described in Lovd as [Pathogenic]. Variant chr15-42399617-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1319G>A	p.Arg440Gln	missense_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1319G>A	p.Arg440Gln	missense_variant	10/23
CAPN3	NM_173087.2	c.1175G>A	p.Arg392Gln	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1319G>A	p.Arg440Gln	missense_variant	10/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000646 AC: 16 AN: 247616 Hom.: 0 AF XY: 0.000105 AC XY: 14 AN XY: 133908

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1458920 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111 AN XY: 725320

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74342

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Experiments in patient-derived samples showed absence or significant reduction in CAPN3 protein level/activity in multiple patients (PMID: 15221789, 17994539, 18055493). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15221789, 18334579, 20694146, 18055493, 15689361, 17236769, 31589614, 21984748, 17994539, 15725583, 30564623, 32906206, 24077912, 32528171, 18854869, 33250842, 19048948, 25326637, 17526799, 33337384, 35169782) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 28, 2020	PS4, PM2, PM3, PM5, PP4 -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the CAPN3 protein (p.Arg440Gln). This variant is present in population databases (rs376107921, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 15221789, 18055493, 19048948, 20694146, 21984748, 25326637). ClinVar contains an entry for this variant (Variation ID: 217147). 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%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 15221789, 18055493, 19048948, 20694146). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 10, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 25, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;.;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
REVEL	Pathogenic	0.79
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D
Vest4		0.84
MVP		0.96
MPC		0.67
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.57
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: rs376107921; hg19: chr15-42691815; COSMIC: COSV58821007; COSMIC: COSV58821007;