rs149095128

Positions:

• chr15-42411299-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.2393C>A​(p.Ala798Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.91

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain EF-hand 4 (size 34) in uniprot entity CAN3_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PP5: Variant 15-42411299-C-A is Pathogenic according to our data. Variant chr15-42411299-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42411299-C-A is described in Lovd as [Pathogenic]. Variant chr15-42411299-C-A is described in Lovd as [Likely_pathogenic]. Variant chr15-42411299-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2393C>A	p.Ala798Glu	missense_variant	23/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2393C>A	p.Ala798Glu	missense_variant	23/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.398C>A	p.Ala133Glu	missense_variant	10/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.398C>A	p.Ala133Glu	missense_variant	10/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.398C>A	p.Ala133Glu	missense_variant	11/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.398C>A	p.Ala133Glu	missense_variant	10/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.296C>A	p.Ala99Glu	missense_variant	10/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2829C>A		non_coding_transcript_exon_variant	25/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2829C>A		3_prime_UTR_variant	25/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251420 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135878

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: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 290 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 727214

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: 0.000257

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 9 AN XY: 74366

Gnomad4 AFR AF: 0.0000483

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: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 798 of the CAPN3 protein (p.Ala798Glu). This variant is present in population databases (rs149095128, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) (PMID: 17994539, 18055493, 18337726, 19556129, 22443334, 23169433, 25135358; Invitae). 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: 92414). 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: 11053681, 17994539, 18055493, 18337726, 19556129, 22443334). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change is predicted to replace alanine with glutamic acid at codon 798 of the CAPN3 protein, p.(Ala798Glu). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the Penta E-F hand (PEF) domain (PMID: 26363099). There is a large physicochemical difference between alanine and glutamic acid. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive condition (rs149095128, 28/282,814 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified homozygous and with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy and segregates with the condition in at least one family (PMID: 18055493, 19556129, 22443334, 25135358, 26886200; LOVD). Absent or reduced calpain 3 protein expression has been identified in the muscle biopsies of multiple cases with the variant (PMID: 18055493, 18337726, 19556129). Multiple lines of computational evidence have conflicting predictions for the missense substitution (2/4 algorithms predict deleterious). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP4. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across eight studies, the CAPN3 c.2393C>A (p.Ala798Glu) missense variant was identified in 11 patients with calpainopathy, including two homozygotes, eight compound heterozygotes, and one heterozygote in whom a second variant was not identified (Anderson et al. 2000; Groen et al. 2007; Duno et al. 2008; Charlton R et al. 2009; Hauerslev et al. 2012; Sveen et al. 2013; Stehlíková et al. 2014; Kuhn et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala798Glu variant is classified as pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 26, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2024	Not observed at significant frequency in large population cohorts (gnomAD); 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: 10330340, 25525159, 37273706, 11053681, 25135358, 27447704, 22443334, 18055493, 17994539, 18337726, 19556129, 26886200, 30919934, 34405919) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

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

Apr 06, 2024

- -

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

Dec 28, 2021

Variant summary: CAPN3 c.2393C>A (p.Ala798Glu) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251420 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8e-05 vs 0.0032), allowing no conclusion about variant significance. c.2393C>A has been reported in the literature in multiple individuals affected with limb girdle muscular dystrophy type 2A (Groen_2007, Guglieri_2008, Duno_2008, Charlton_2009, Hauerslev_2012), including at least one homozygote. These data indicate that the variant is very likely to be associated with disease. Western blot results showed reduced or absent Calpain-3 protein at 94kDa and 30kDa from patients samples who carried this variant (Groen_2007, Guglieri_2008, Duno_2008, Charlton_2009, Hauerslev_2012). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T;.;.;T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;T;D;D;D;.;T;.;D;.
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.6	.;.;.;L;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	.;N;N;N;D;D;D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.15	.;T;T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.98	T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.98	.;D;D;D;.;.;.;.;.;.;.
Vest4		0.88
MVP		0.99
MPC		0.68
ClinPred		0.83	D
GERP RS		6.2
Varity_R		0.49
gMVP		0.81

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: rs149095128; hg19: chr15-42703497;