rs767106920

Positions:

• chr15-42394325-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. 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).

• 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:4 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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• 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=4, Pathogenic=2, Likely_pathogenic=1}. 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	Protein	UniProt
CAPN3	NM_000070.3	c.1099G>A	p.Gly367Ser	missense_variant	8/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1099G>A	p.Gly367Ser	missense_variant	8/23		NP_077320.1
CAPN3	NM_173087.2	c.955G>A	p.Gly319Ser	missense_variant	7/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1099G>A	p.Gly367Ser	missense_variant	8/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*895G>A		non_coding_transcript_exon_variant	12/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*895G>A		3_prime_UTR_variant	12/26	2		ENSP00000492063.1

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:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2024	Identified in the single heterozygous state without a second identified CAPN3 variant in a patient with proximal muscle weakness and myopathy, however, this individual was found to be homozygous for a variant in a different gene that may explain the majority of the phenotype (PMID: 33250842); 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: 34201303, 15689361, 32403337, 17236769, 25079074, 16627476, 33250842) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 17, 2021	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 14, 2024

- -

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
MutationAssessor	Uncertain	2.8	.;M;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	.;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;D;D;D
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;