rs201736037

chr15-42401721-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_000070.3(CAPN3):c.1435A>G(p.Ser479Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,614,052 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. S479S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.90

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 12 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, 4 uncertain in NM_000070.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 15-42401721-A-G is Pathogenic according to our data. Variant chr15-42401721-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42401721-A-G is described in Lovd as [Pathogenic]. Variant chr15-42401721-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1435A>G	p.Ser479Gly	missense_variant	11/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1435A>G	p.Ser479Gly	missense_variant	11/23
CAPN3	NM_173087.2	c.1291A>G	p.Ser431Gly	missense_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1435A>G	p.Ser479Gly	missense_variant	11/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152176 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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251424 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135882

Gnomad AFR exome AF: 0.0000615

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: 0.0000462

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80 AN XY: 727238

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: 0.0000187

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74312

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000574 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 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: 18055493, 27055500, 11166169, 20694146, 27066573, 11297944, 30564623, 34426522, 31589614, 34298987, 18563459, 15689361, 10330340, 32896923) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 479 of the CAPN3 protein (p.Ser479Gly). This variant is present in population databases (rs201736037, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 15689361, 18055493, 18563459, 20694146). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92405). 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 expected to disrupt CAPN3 protein function with a positive 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

Sep 19, 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

Mar 18, 2022

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 11, 2022

Variant summary: CAPN3 c.1435A>G (p.Ser479Gly) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251424 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.1435A>G has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, specifically Limb-girdle muscular dystrophy type 2A (LGMD2A) (example, Richard_1999, Saenz_2005, Groen_2007, Blazquez_2008, de Morree_2010, Izumi_2015, Toral-Ojeda_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
REVEL	Pathogenic	0.89
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.97, 0.92, 0.97	.;D;P;D
Vest4		0.90
MVP		0.94
MPC		0.15
ClinPred		0.40	T
GERP RS		4.5
Varity_R		0.74
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201736037; hg19: chr15-42693919;