rs775453643

Variant names:

• chr15-42396801-T-C
• rs775453643
• NM_000070.3:c.1117T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000070.3(CAPN3):​c.1117T>C​(p.Trp373Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense, splice_region
• Scores: Splicing: ADA: 0.8019
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:4
• Conservation: PhyloP100: 5.81
• Publications: 2 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 15-42396801-T-C is Pathogenic according to our data. Variant chr15-42396801-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217145.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1117T>C	p.Trp373Arg	missense_variant, splice_region_variant	Exon 9 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1117T>C	p.Trp373Arg	missense_variant, splice_region_variant	Exon 9 of 23		NP_077320.1
CAPN3	NM_173087.2	c.973T>C	p.Trp325Arg	missense_variant, splice_region_variant	Exon 8 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1117T>C	p.Trp373Arg	missense_variant, splice_region_variant	Exon 9 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*913T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*913T>C		3_prime_UTR_variant	Exon 13 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460722 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726734

African (AFR) AF: 0.0000897 AC: 3 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110972

Other (OTH) AF: 0.0000331 AC: 2 AN: 60362

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000465 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:8 Uncertain:2

Mar 10, 2023

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified in an homozygous state in a patient with limb-girdle muscular dystrophy -

Oct 10, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 28, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive CAPN3-related muscular dystrophy. A dominant-negative mechanism has also been suggested for autosomal dominant CAPN3-related muscular dystrophy (PMID: 32342993). (I) 0108 - This gene is associated with both recessive and dominant disease. Loss of function variants are usually inherited in a recessive manner, resulting in a severe phenotype however, a number of in-frame deletions and missense variants have more recently been described to result in a milder, later-onset calpainopathy phenotype with autosomal dominant inheritance (PMIDs: 32557990, 32342993). (I) 0115 - Variants in this gene are known to have variable expressivity. Some heterozygous carriers only present with isolated hyperCKaemia (PMID: 32557990). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated catalytic domain (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in two homozygous siblings with limb-girdle muscular dystrophy 2A and also reported with conflicting interpretation from VUS to pathogenic (ClinVar, PMID: 18337726). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1,PM2,PM3,PP2,PP3 -

Feb 10, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PP2, PP3, PP5 -

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 373 of the CAPN3 protein (p.Trp373Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 18337726, 30564623; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217145). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 18258189). For these reasons, this variant has been classified as Pathogenic. -

Jul 06, 2024

Inheritance Genetic Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 04, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6 Uncertain:2

May 23, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Individual homozygous for the W373R variant was found to have absent CAPN3 protein on western blot (Duno et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18258189, 16627476, 33281875, 22443334, 18337726, 30564623, 32528171, 27535533, 33726816) -

Dec 28, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAPN3: PM2, PM3 -

Feb 07, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 05, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.1	.;L;.;L
PhyloP100		5.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	.;N;N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.015	.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.41, 0.14, 0.46	.;B;B;P
Vest4		0.84
MutPred		0.86		.;Gain of disorder (P = 0.0059);.;Gain of disorder (P = 0.0059);
MVP		0.98
MPC		0.49
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.91
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.45
Splicevardb		2.0
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775453643; hg19: chr15-42688999;