rs1555420634

Positions:

• chr15-42388996-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000070.3(CAPN3):​c.701G>A​(p.Gly234Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G234R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.90

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42388995-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1701252.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 15-42388996-G-A is Pathogenic according to our data. Variant chr15-42388996-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 501754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42388996-G-A is described in Lovd as [Pathogenic]. Variant chr15-42388996-G-A is described in Lovd as [Pathogenic]. Variant chr15-42388996-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.701G>A	p.Gly234Glu	missense_variant	5/24	ENST00000397163.8
CAPN3	NM_024344.2	c.701G>A	p.Gly234Glu	missense_variant	5/23
CAPN3	NM_173087.2	c.701G>A	p.Gly234Glu	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.701G>A	p.Gly234Glu	missense_variant	5/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Gly234Glu variant in CAPN3 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies with a yeast two-hybrid model provide some evidence that the p.Gly234Glu variant may impact protein function by impairing protein binding with substrates (PMID: 9642272). However, these types of assays may not accurately represent biological function. The p.Gly234Glu variant in CAPN3 has been reported in 5 individuals with Limb-Girdle Muscular Dystrophy. The presence of this variant in combination with 4 variants (including a frameshift variant) reported pathogenic by the literature and in 4 of these individuals with LGMD increases the likelihood that the p.Gly234Glu variant is pathogenic (PMID: 16141003, 17994539, 27500519). This variant has also been reported pathogenic in ClinVar (Variation ID: 501754). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate, PM3_Strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2022	This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). 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. ClinVar contains an entry for this variant (Variation ID: 501754). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 234 of the CAPN3 protein (p.Gly234Glu). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 24, 2017	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Feb 23, 2022	PP3, PM2_SUP, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.56, 0.26, 0.61	.;P;B;P
Vest4		0.98
MutPred		0.98		Loss of catalytic residue at V235 (P = 0.0724);Loss of catalytic residue at V235 (P = 0.0724);Loss of catalytic residue at V235 (P = 0.0724);Loss of catalytic residue at V235 (P = 0.0724);
MVP		0.98
MPC		0.43
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.98

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: rs1555420634; hg19: chr15-42681194;