rs553169803

chr15-42409835-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000070.3(CAPN3):c.2041G>A(p.Val681Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,350,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V681A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000076 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.22

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain EF-hand 1 (size 34) in uniprot entity CAN3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.25755763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2041G>A	p.Val681Met	missense_variant	18/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2041G>A	p.Val681Met	missense_variant	18/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000762 AC: 10 AN: 131208 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000268

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000790

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251162 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135784

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 20 AN: 1219574 Hom.: 0 Cov.: 38 AF XY: 0.0000197 AC XY: 12 AN XY: 607754

Gnomad4 AFR exome AF: 0.0000746

Gnomad4 AMR exome AF: 0.0000510

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000451

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000509

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000762 AC: 10 AN: 131268 Hom.: 0 Cov.: 29 AF XY: 0.0000482 AC XY: 3 AN XY: 62192

Gnomad4 AFR AF: 0.000112

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000267

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000790

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000389 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 681 of the CAPN3 protein (p.Val681Met). This variant is present in population databases (rs553169803, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 536514). 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. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2020	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.019	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
REVEL	Uncertain	0.38
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.99	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.54
MVP		0.91
MPC		0.50
ClinPred		0.44	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.30

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: rs553169803; hg19: chr15-42702033; COSMIC: COSV55513612; COSMIC: COSV55513612;