rs140425651

chr15-42409951-G-Achr15-42409951-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP3 BP4_Strong BP6

The NM_000070.3(CAPN3):c.2071G>A(p.Gly691Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,612,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. G691G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 8.11

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a region_of_interest Domain IV (size 171) in uniprot entity CAN3_HUMAN there are 116 pathogenic changes around while only 4 benign (97%) in NM_000070.3
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, FATHMM_MKL, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.06506458).
• BP6: Variant 15-42409951-G-A is Benign according to our data. Variant chr15-42409951-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281011.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2071G>A	p.Gly691Arg	missense_variant	19/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2071G>A	p.Gly691Arg	missense_variant	19/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152070 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251388 Hom.: 1 AF XY: 0.000177 AC XY: 24 AN XY: 135866

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.0000760 AC: 111 AN: 1460174 Hom.: 0 Cov.: 34 AF XY: 0.0000661 AC XY: 48 AN XY: 726338

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000681

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152188 Hom.: 1 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74390

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000416 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 691 of the CAPN3 protein (p.Gly691Arg). This variant is present in population databases (rs140425651, gnomAD 0.09%). 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: 281011). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.	Apr 17, 2020	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 29, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.083	T;.;.;D;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
REVEL	Pathogenic	0.92
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.61		.;.;.;Gain of MoRF binding (P = 0.0314);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		0.62
ClinPred		0.086	T
GERP RS		4.8
Varity_R		0.55
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140425651; hg19: chr15-42702149; COSMIC: COSV55520484; COSMIC: COSV55520484;