rs750083132

chr15-42410633-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000070.3(CAPN3):c.2230A>G(p.Ser744Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,838 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. S744T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 4.26

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 9 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, 6 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 15-42410633-A-G is Pathogenic according to our data. Variant chr15-42410633-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555001.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr15-42410633-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2230A>G	p.Ser744Gly	missense_variant	21/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2230A>G	p.Ser744Gly	missense_variant	21/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251302 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2021	This variant is present in population databases (rs750083132, ExAC 0.002%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change causes constitutive autolysis (PMID: 9642272). This variant has been observed to segregate with limb-girdle muscular dystrophy in several families (PMID: 7720071, 8624690, 9655129). ClinVar contains an entry for this variant (Variation ID: 555001). This sequence change replaces serine with glycine at codon 744 of the CAPN3 protein (p.Ser744Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	Consanguinity: No Clinical Indications: Difficulty climbing stairs and lifting objects since 5 years, waddling gait, Power- weak biceps, weak lower limb adduction Investigations: CPK - 1487 U/L Family history: Sister is similarly affected Clinical Suspicion: Limb Girdle Muscular Dystrophy -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 06, 2022

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 10, 2023

Variant summary: CAPN3 c.2230A>G (p.Ser744Gly) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251302 control chromosomes. c.2230A>G has been reported in the literature in at-least three individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive as being a compound heterozygous state along with two different pathogenic variants, respectively (examples: Anderson_1998, Ono_1998, Penisson-Besnier_1998, Richard_1995). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in completely loss of proteolysis activity against the substrate fodrin (Richard_1995). Additionally, significantly decreased CAPN3 levels in muscular biopsy, determined by Western blotting, have been found in at-least two patients carrying c.2230A>G and second null alleles, respectively (Anderson_1998). These data indicate that the variant is very likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9777948, 9642272, 9655129, 7720071). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic n=2; VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.057	T;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
REVEL	Pathogenic	0.72
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.87		.;.;.;Loss of disorder (P = 0.1102);.;.;.;.;.;.;.;.;
MVP		0.87
MPC		0.60
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.77
gMVP		0.73

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: rs750083132; hg19: chr15-42702831;