GeneBe

CPAMD8

protein-coding

C3 and PZP like alpha-2-macroglobulin domain containing 8, the group of C3 and PZP like, alpha-2-macroglobulin domain containing

Gene summary

This gene encodes a member of the protease inhibitor I39 (alpha-2-macroglobulin) family of proteins. These proteins are important in innate and acquired immunity. The encoded protein is membrane-associated and proteolytically processed to generate two chains. Mutations in this gene cause a form of anterior segment dysgenesis, a developmental disorder of the eye. [provided by RefSeq, May 2017]

MANE transcript

NM_015692.5

Inheritance

AR

ClinVar variants

P:38U:380B:165

Top phenotype

Anterior segement dysgenesis 8

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr19:16,892,951-17,026,815

External References & Databases

Ensembl (ENSG00000160111)NCBI Gene (27151)OMIM (608841)HGNC:23228GenCCUniProt (Q8IZJ3)AlphaFoldClinVar (CPAMD8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~133.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

anterior segment dysgenesis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015017

Submitter: G2P

anterior segment dysgenesis 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0015017

Submitter: Ambry Genetics

anterior segment dysgenesis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015017

Submitter: Labcorp Genetics (formerly Invitae)

anterior segment dysgenesis 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015017

Submitter: ClinGen

*CPAMD*8 was first reported in relation to autosomal recessive anterior segment dysgenesis 8 (ASD8) in 2016 (Cheong et al., PMID: 27839872). ASD disorders include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Individuals with *CPAMD8* variants are described with glaucoma and features of ASD or with isolated ASD, however, with a high degree of variability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in Anterior Segment Dysgenesis 8 (ASD8; OMIM: 617319) and Open-Angle Glaucoma (OMIM: 137750) associated with *CPAMD8*. Therefore these disease entities have been lumped into a single entity, *CPAMD8*-related anterior segment dysgenesis. Summary of Genetic Evidence: Eight missense, three nonsense, four frameshift, five splice-site and intronic, one in-frame insertion, two large deletion and duplication variants have been reported in 13 probands across three publications (PMIDs: 32085876, 32274568, 27839872). One large deletion was found in one proband in one publication (PMID: 32274568). The exon 23 deletion (c.2794_­­­­2845del) variant is reported in proband CG-ASD-ANI-0066 (PMID:32274568) was not scored in the GCI as the exact breakpoints are unknown; however the variant likely causes a frameshift and warrants 1.5 points. One large duplication spanning exons 8 to 13 reported in (PMID: 32085876).WaS too large to register in the ClinGen Allele Registry and; therefore, could not be scored in the GCI, but warrants 1.5 points. More evidence is available in the literature (PMID: 29556725), but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss of function. Summary of Experimental Evidence: This gene-disease association is also supported by animal models and expression studies (32274568, 27839872, 28683140). The expression study (PMID: 27839872) showed *CPAMD8* detected in the developing human lens and retina at week 9 of gestation into the second trimester. *CPAMD8* was also detected in the iris and cornea at week 22 of gestation. Zebrafish embryos replicated the corneal thickening and abnormal collagen deposition that were found in probands (PMID: 32274568). *CPAMD8* was detected in the epithelium of the ciliary body in fetal and adult cattle (PMID:28683140). In summary, *CPAMD8* is definitively associated with autosomal recessive anterior segment dysgenesis 8. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Anterior segement dysgenesis 8AR

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: 27839872Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CPAMD8 variants in ClinVar

12 Conditions Cataloged
Inborn genetic diseasesTotal: 361
not providedTotal: 264
not specifiedTotal: 46
CPAMD8-related disorderTotal: 44
Anterior segment dysgenesis 8Total: 30
CPAMD8-related disordersTotal: 6
Anterior segment dysgenesisTotal: 2
Glaucoma 3ATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015692.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
79
clinvar
19
clinvar
 100
missense
2
clinvar
2
clinvar
374
clinvar
45
clinvar
22
clinvar
 445
nonsense
5
clinvar
7
clinvar
 12
start loss
0
frameshift
4
clinvar
8
clinvar
 12
splice donor/acceptor (+/-2bp)
2
clinvar
8
clinvar
4
clinvar
 14
Total132538012441583

Highest pathogenic variant AF is 0.0001698953

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015692.5RefSeqNP_056507.342MANE Select
ENST00000443236.7EnsemblENSP00000402505.342MANE Select
ENST00000291440.4EnsemblENSP00000291440.414Standard
ENST00000598792.2EnsemblENSP00000473216.22Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • eye development
  • negative regulation of endopeptidase activity

Molecular Function

  • serine-type endopeptidase inhibitor activity

Cellular Component

  • extracellular space
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000443236
Coding exons
42
Length
133868
Individuals with no LoFs
124613
Homozygous LoFs
0
Heterozygous LoFs
228
Defined
124841
p
0.000914
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.16710941.11e+30.9860.000067812339
Missense (PolyPhen)351380.270.923034496
Synonymous0.2134714770.9880.00003223977
Loss of Function4.275398.80.5360.000005371030

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000460.00045rare
Latino/Admixed American0.000840.00084rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.00110.0011notable
Finnish0.000230.00023rare
European (Non-Finnish)0.00130.0012notable
South Asian0.000690.00069rare
Other0.000830.00082rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease
DISEASE: Anterior segment dysgenesis 8 (ASGD8) [MIM:617319]: A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. ASGD8 patients predominantly manifest iris and lens abnormalities, in the absence of retinal abnormalities or extra-ocular features. ASGD8 transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:27839872}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.105

Intolerance Scores

LoFtool
0.912
RVIS EVS
2.44
RVIS percentile EVS
98.55

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.696

Gene Damage Prediction

AllRecessiveDominant
MendelianHighMediumHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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