C2

protein-coding

complement C2, the group of Complement system activation components|Sushi domain containing

Gene summary

Component C2 is a serum glycoprotein that functions as part of the classical pathway of the complement system. Activated C1 cleaves C2 into C2a and C2b. The serine proteinase C2a then combines with complement factor 4b to create the C3 or C5 convertase. Deficiency of C2 has been reported to associated with certain autoimmune diseases and SNPs in this gene have been associated with altered susceptibility to age-related macular degeneration. This gene localizes within the class III region of the MHC on the short arm of chromosome 6. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described in publications but their full-length sequence has not been determined.[provided by RefSeq, Mar 2009]

MANE transcript

NM_000063.6

Inheritance

ClinVar variants

P:30U:202B:132

Top phenotype

Complement component 2 deficiency

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr6:31,897,785-31,945,673

External References & Databases

Ensembl (ENSG00000166278)

Transcript & Mutation Effects

hg38 • Region Span ~47.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complement component 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009006

Submitter: Labcorp Genetics (formerly Invitae)

complement component 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009006

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Complement component 2 deficiencyAR

Manifestation: Allergy/Immunology/Infectious; Renal

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial for infectious manifestations; Patients may also develop autoimmune manifestations, and treatment with immune modulators has been described

Refs: 14446782; 4161820; 1124106; 2582254; 1542325; 1361318; 1577763; 8621452; 15643297; 16026838; 20417301; 20890976; 22842196

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 366

not specifiedTotal: 100

Complement component 2 deficiencyTotal: 50

Age related macular degeneration 14Total: 46

C2-related disorderTotal: 7

C2 deficiency, type IITotal: 2

Macular degenerationTotal: 1

Atypical hemolytic-uremic syndrome with B factor anomalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000063.6. 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	1 clinvar		5 clinvar	98 clinvar	1 clinvar	105
missense	1 clinvar		194 clinvar	32 clinvar		227
nonsense	6 clinvar	1 clinvar	3 clinvar			10
start loss						0
frameshift	9 clinvar	2 clinvar				11
splice donor/acceptor (+/-2bp)	1 clinvar	9 clinvar		1 clinvar		11
Total	18	12	202	131	1	364

Highest pathogenic variant AF is 0.0057364567

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000063.6	RefSeq	NP_000054.2	18	MANE Select
ENST00000299367.10	Ensembl	ENSP00000299367.5	18	MANE Select
NM_001145903.3	RefSeq	NP_001139375.1	16	Standard
NM_001178063.3	RefSeq	NP_001171534.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)
Staphylococcus aureus infection - Homo sapiens (human)
Allograft Rejection

Biological Process

proteolysis
complement activation
complement activation, classical pathway
response to nutrient
regulation of complement activation

Molecular Function

serine-type endopeptidase activity
protein binding
metal ion binding

Cellular Component

extracellular region
extracellular space
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299367
Coding exons: 18
Length: 47888
Individuals with no LoFs: 124496
Homozygous LoFs: 2
Heterozygous LoFs: 1250
Defined: 125748
p: 0.00499

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.12	361	426	0.847	0.0000266	4954
Missense (PolyPhen)		128	169.65	0.75448		1985
Synonymous	1.06	151	168	0.896	0.0000108	1478
Loss of Function	1.42	30	39.6	0.757	0.00000232	421

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0010	notable
Latino/Admixed American	0.0040	0.0040	notable
Ashkenazi Jewish	0.012	0.012	notable
East Asian	0.00027	0.00027	rare
Finnish	0.0052	0.0051	notable
European (Non-Finnish)	0.0073	0.0073	notable
South Asian	0.00056	0.00056	rare
Other	0.0044	0.0044	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component C2 which is part of the classical pathway of the complement system is cleaved by activated factor C1 into two fragments: C2b and C2a. C2a, a serine protease, then combines with complement factor C4b to generate the C3 or C5 convertase.;
Disease: DISEASE: Complement component 2 deficiency (C2D) [MIM:217000]: A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus erythematosus. Skin and joint manifestations are common and renal disease is relatively rare. Patients with complement component 2 deficiency are also reported to have recurrent invasive infections. {ECO:0000269|PubMed:8621452, ECO:0000269|PubMed:9670930}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.133

Intolerance Scores

LoFtool: 0.260
RVIS EVS: -0.07
RVIS percentile EVS: 48.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.895

Gene Damage Prediction

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