rs767106920

chr15-42394325-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000070.3(CAPN3):c.1099G>A(p.Gly367Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,408,370 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G367NKNRC) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 9.63

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000070.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 15-42394325-G-A is Pathogenic according to our data. Variant chr15-42394325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468639.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=1, Pathogenic=2}. Variant chr15-42394325-G-A is described in Lovd as [Pathogenic]. Variant chr15-42394325-G-A is described in Lovd as [Pathogenic]. Variant chr15-42394325-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.1099G>A	p.Gly367Ser	missense_variant	8/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1099G>A	p.Gly367Ser	missense_variant	8/23
CAPN3	NM_173087.2	c.955G>A	p.Gly319Ser	missense_variant	7/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1099G>A	p.Gly367Ser	missense_variant	8/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000536 AC: 9 AN: 167974 Hom.: 0 AF XY: 0.0000451 AC XY: 4 AN XY: 88790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000811

Gnomad SAS exome AF: 0.000215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000296

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 40 AN: 1408370 Hom.: 0 Cov.: 31 AF XY: 0.0000345 AC XY: 24 AN XY: 695554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000817

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.000288

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000932 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000345 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 367 of the CAPN3 protein (p.Gly367Ser). This variant is present in population databases (rs767106920, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 25079074, 32403337, 33250842; Invitae). ClinVar contains an entry for this variant (Variation ID: 468639). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CAPN3 function (PMID: 17236769). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 17, 2023

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 31, 2022

Variant summary: CAPN3 c.1099G>A (p.Gly367Ser) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 199358 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.5e-05 vs 0.0032), allowing no conclusion about variant significance. c.1099G>A has been reported in the literature as a biallelic genotype in individuals affected with Limb-Girdle Muscular Dystrophy (Saenz_2005, Milic_2007, Nilsson_2014, Gonzalez-Quereda_2020). These data indicate that the variant is likely to be associated with disease. In vitro analysis of muscle biopsy homogenate from a patient demonstrated normal cleavage activity, however the authors suggest that other functional characteristics may be deficient as they only assayed whole tissue homogenates (Milic_2007). Three ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.98
MVP		0.99
MPC		0.63
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.96

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: rs767106920; hg19: chr15-42686523; COSMIC: COSV58824883;