CAPN5

protein-coding

calpain 5, the group of Calpains|C2 domain containing

Gene summary

Calpains are calcium-dependent cysteine proteases involved in signal transduction in a variety of cellular processes. A functional calpain protein consists of an invariant small subunit and 1 of a family of large subunits. CAPN5 is one of the large subunits. Unlike some of the calpains, CAPN5 and CAPN6 lack a calmodulin-like domain IV. Because of the significant similarity to Caenorhabditis elegans sex determination gene tra-3, CAPN5 is also called as HTRA3. [provided by RefSeq, Jul 2008]

Previous symbols:

VRNI

MANE transcript

NM_004055.5

Inheritance

ClinVar variants

P:4U:398B:237

Top phenotype

Vitreoretinopathy, neovascular inflammatory

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr11:77,066,961-77,126,155

External References & Databases

Ensembl (ENSG00000149260)

Transcript & Mutation Effects

hg38 • Region Span ~59.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant neovascular inflammatory vitreoretinopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008664

Submitter: Ambry Genetics

CAPN5-related vitreoretinopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100450

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant neovascular inflammatory vitreoretinopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008664

Submitter: Orphanet

CAPN5-related vitreoretinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100450

Submitter: G2P

CAPN5-related vitreoretinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100450

Submitter: ClinGen

CAPN5 was first reported in relation to autosomal dominant CAPN5-related vitreoretinopathy in 2012 in a patient described with described as neovascular inflammatory vitreoretinopathy, (Mahajan et al, PMID: 23055945). Six variants (all missense), reported in 10 probands in 6 publications (Mahajan et al, 2012, PMID: 23055945; Bassuk et al, 2015, PMID: 25856303; Randazzo et al, 2017, PMID: 29040051; Velez et al, 2018, PMID: 29472286; O’Keefe et al, 2019, PMID: 30986125; Tang et al, 2020, PMID: 32274441) are included in this curation, in addition to segregation data from analysis of a large family (Stone et al, 1992, PMID: 1284594) (Total Genetic Evidence: 7.8 points). This gene-disease association is also supported by experimental evidence including expression data from RNA-Seq analysis (Schaefer et al, 2016, PMID: 27152965) and the phenotype observed in mouse models (Wert et al, 2014, PMID: 24381307; Wert et al, 2015, PMID: 25994508). In summary, CAPN5 is definitively associated with autosomal dominant CAPN5-related vitreoretinopathy. This classification was approved by the ClinGen Retina GCEP on August 5, 2021.

Clinical Genomic Database (CGD)

Vitreoretinopathy, neovascular inflammatoryAD

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23055945

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAPN5 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 698

not specifiedTotal: 220

Inborn genetic diseasesTotal: 131

CAPN5-related disorderTotal: 31

Retinal dystrophyTotal: 13

Proliferative vitreoretinopathyTotal: 9

Autosomal dominant neovascular inflammatory vitreoretinopathyTotal: 5

High myopiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004055.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	165 clinvar	4 clinvar	179
missense	4 clinvar		337 clinvar	65 clinvar	1 clinvar	407
nonsense			18 clinvar	1 clinvar		19
start loss						0
frameshift			19 clinvar	1 clinvar		20
splice donor/acceptor (+/-2bp)			14 clinvar			14
Total	4	0	398	232	5	639

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004055.5	RefSeq	NP_004046.2	12	MANE Select
ENST00000648180.1	Ensembl	ENSP00000498132.1	12	MANE Select
NM_001425321.1	RefSeq	NP_001412250.1	13	Standard
NM_001425322.1	RefSeq	NP_001412251.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrin-mediated Cell Adhesion
Extracellular matrix organization
Degradation of the extracellular matrix

Biological Process

proteolysis
signal transduction

Molecular Function

calcium-dependent cysteine-type endopeptidase activity

Cellular Component

cytoplasm
focal adhesion
cell surface
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000278559
Coding exons: 12
Length: 59223
Individuals with no LoFs: 125624
Homozygous LoFs: 0
Heterozygous LoFs: 124
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.534	394	425	0.927	0.0000295	4179
Missense (PolyPhen)		158	188.81	0.83684		1866
Synonymous	0.0735	177	178	0.993	0.0000129	1250
Loss of Function	2.56	18	34.1	0.527	0.00000190	345

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00075	0.00074	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.00076	0.00076	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00054	0.00054	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-regulated non-lysosomal thiol-protease. {ECO:0000250}.;
Disease: DISEASE: Vitreoretinopathy, neovascular inflammatory (VRNI) [MIM:193235]: An autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. Patients present during the second or third decade of life with posterior uveitis and reduction of the electroretinogram b-wave. They become more symptomatic when cataracts, cystoid macular edema, and disk edema diminish visual acuity during the second stage. Severe vision loss begins during the third stage when proliferative retinal neovascularization and epiretinal membranes appear. There is an ongoing pigmentary retinal degeneration and peripheral visual field loss during all stages. In the fourth stage, proliferative vitreoretinopathy causes tractional retinal detachments at the macula and vitreous base. The fifth or end- stage disease is marked by phthisis. {ECO:0000269|PubMed:23055945}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.214
RVIS EVS: -0.9
RVIS percentile EVS: 10.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.392

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium