CPN1

protein-coding

carboxypeptidase N subunit 1, the group of M14 carboxypeptidases

Gene summary

Carboxypeptidase N is a plasma metallo-protease that cleaves basic amino acids from the C terminal of peptides and proteins. The enzyme is important in the regulation of peptides like kinins and anaphylatoxins, and has also been known as kininase-1 and anaphylatoxin inactivator. This enzyme is a tetramer comprised of two identical regulatory subunits and two identical catalytic subunits; this gene encodes the catalytic subunit. Mutations in this gene can be associated with angioedema or chronic urticaria resulting from carboxypeptidase N deficiency. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001308.3

Inheritance

ClinVar variants

P:2U:54B:7

Top phenotype

Carboxypeptidase N deficiency

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr10:100,042,193-100,081,869

External References & Databases

Ensembl (ENSG00000120054)

Transcript & Mutation Effects

hg38 • Region Span ~39.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

carboxypeptidase N deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008910

Submitter: G2P

carboxypeptidase N deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008910

Submitter: Illumina

Clinical Genomic Database (CGD)

Carboxypeptidase N deficiencyAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may have recurrent urticaria and peripheral angioedema, sometimes due to recognized triggers, and awareness may allow preventative measures as well (including avoidance of triggers) as well as prompt and appropriate treatment of episodes

Comments: Heterozygotes may demonstrate milder manifestations

Refs: 7437116; 12560874; 18068674; 38445235

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CPN1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 57

Anaphylotoxin inactivator deficiencyTotal: 2

not providedTotal: 1

Hereditary angioedema with normal C1InhTotal: 1

CPN1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001308.3. 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					2 clinvar	2
missense		1 clinvar	53 clinvar	5 clinvar		59
nonsense						0
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	1	54	5	2	63

Highest pathogenic variant AF is 0.00009851301

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001308.3	RefSeq	NP_001299.1	9	MANE Select
ENST00000370418.8	Ensembl	ENSP00000359446.3	9	MANE Select
ENST00000441382.1	Ensembl	ENSP00000410895.1	5	Standard
ENST00000877010.1	Ensembl	ENSP00000547069.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Androgen Receptor Network in Prostate Cancer
Human Complement System
Steroid Biosynthesis
Innate Immune System
Immune System

Biological Process

peptide metabolic process
bradykinin catabolic process
protein processing
regulation of complement activation
response to glucocorticoid

Molecular Function

metallocarboxypeptidase activity
zinc ion binding

Cellular Component

extracellular region
extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370418
Coding exons: 9
Length: 39685
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.342	263	279	0.942	0.0000186	3016
Missense (PolyPhen)		114	124.81	0.91336		1312
Synonymous	-1.40	133	114	1.17	0.00000837	881
Loss of Function	1.34	14	20.6	0.680	9.51e-7	231

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00092	0.00091	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protects the body from potent vasoactive and inflammatory peptides containing C-terminal Arg or Lys (such as kinins or anaphylatoxins) which are released into the circulation.;

Recessive Scores

pRec: 0.273

Intolerance Scores

LoFtool: 0.716
RVIS EVS: -0.56
RVIS percentile EVS: 19.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.872

Gene Damage Prediction

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