rs863224959

Positions:

• chr15-42402971-C-G
• chr15-42402971-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000070.3(CAPN3):​c.1714C>G​(p.Arg572Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R572P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.17

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 region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42402972-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1714C>G	p.Arg572Gly	missense_variant	13/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1714C>G	p.Arg572Gly	missense_variant	13/23		NP_077320.1
CAPN3	NM_173087.2	c.1570C>G	p.Arg524Gly	missense_variant	12/21		NP_775110.1
CAPN3	NM_173088.2	c.178C>G	p.Arg60Gly	missense_variant	2/13		NP_775111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1714C>G	p.Arg572Gly	missense_variant	13/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*2168C>G		non_coding_transcript_exon_variant	16/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2168C>G		3_prime_UTR_variant	16/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2022

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: 498261). This missense change has been observed in individual(s) with clinical features of limb girdle muscular dystrophy (PMID: 30564623). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 572 of the CAPN3 protein (p.Arg572Gly). This variant disrupts the p.Arg572 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 10102422, 16650086, 27066545, 27708273). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.8	.;H;.;H;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.6	.;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.97
MutPred		0.91		.;Gain of methylation at K577 (P = 0.0335);.;Gain of methylation at K577 (P = 0.0335);.;.;
MVP		0.95
MPC		0.72
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.94

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: rs863224959; hg19: chr15-42695169;