rs200646556

Positions:

• chr15-42399548-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000070.3(CAPN3):​c.1250C>T​(p.Thr417Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,613,410 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T417T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 15-42399548-C-T is Pathogenic according to our data. Variant chr15-42399548-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399548-C-T is described in Lovd as [Pathogenic]. Variant chr15-42399548-C-T is described in Lovd as [Pathogenic]. Variant chr15-42399548-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1250C>T	p.Thr417Met	missense_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1250C>T	p.Thr417Met	missense_variant	10/23
CAPN3	NM_173087.2	c.1106C>T	p.Thr369Met	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1250C>T	p.Thr417Met	missense_variant	10/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251420 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135888

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461282 Hom.: 0 Cov.: 30 AF XY: 0.0000949 AC XY: 69 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74308

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CAPN3: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2020	The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 30, 2021	PS3, PM2, PS4_moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 12, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	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: 25135358, 19226146, 15689361, 19556129, 25214167, 25079074, 16650086, 32703463, 29792937, 31788660, 32528171, 32668095, Koken_2022_Abstract, 34440373) -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 417 of the CAPN3 protein (p.Thr417Met). This variant is present in population databases (rs200646556, gnomAD 0.008%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 20517216, 25079074, 25135358). ClinVar contains an entry for this variant (Variation ID: 281505). 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 affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Thr417Met variant in CAPN3 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD) Trio exome analysis showed this variant to be de novo. The p.Thr417Met variant in CAPN3 has been reported in 4 individuals (including 1 French, 1 European Canadian individual) with LGMD (PMID: 25135358, 25079074,16650086), and has been identified in 0.008324% (2/24026) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200646556). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Animal models in rats have shown that this variant impacts calcium binding for the protein and causes LGMD (PMID: 19226146). The presence of this variant in combination with 2 reported pathogenic variants, p.Thr184Argfs and p.Glu622Argfs, and in 2 individuals with LGMD increases the likelihood that the p.Thr417Met variant is pathogenic (Variation ID: 17621, 290296). This variant has also been reported pathogenic in ClinVar (Variation ID: 281505). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant, functional evidence, and multiple occurrences with pathogenic CAPN3 variants in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PS2, PP3, PM3_Strong, PS3_Moderate (Richards 2015). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

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

Dec 02, 2022

Variant summary: CAPN3 c.1250C>T (p.Thr417Met) 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 5.2e-05 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.2e-05 vs 0.0032), allowing no conclusion about variant significance. c.1250C>T has been reported in the literature as biallelic genotypes in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, PMID: 15689361, 18258189, 25135358, 27447704, 34440373, 25079074, 16650086). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
REVEL	Pathogenic	0.90
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.93
MVP		0.97
MPC		0.64
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.84

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: rs200646556; hg19: chr15-42691746; COSMIC: COSV58826190; COSMIC: COSV58826190;