C4B

complement C4B (Chido blood group), the group of C3 and PZP like, alpha-2-macroglobulin domain containing|Complement system activation components|Blood group antigens

Basic information

Region (hg38): 6:32014794-32035418

Links

ENSG00000224389 ∙ NCBI:721 ∙ OMIM:120820 ∙ HGNC:1324 ∙ Uniprot:P0C0L5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complement component 4b deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Complement component 4B deficiency	AR	General	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	Allergy/Immunology/Infectious	4190973; 7451653; 2862466; 3501712; 3260957; 3265961; 2551816; 2384609; 1401055; 20580617; 22387014; 29928053

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the C4B gene.

• Inborn genetic diseases (21 variants)
• not specified (4 variants)
• Complement component 4b deficiency (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the C4B gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous					1	1
missense			22		2	24
nonsense						0
start loss						0
frameshift					1	1
inframe indel						0
splice donor/acceptor (+/-2bp)		1				1
splice region						0
non coding					1	1
Total	0	1	22	0	5

Highest pathogenic variant AF is 0.0000330

Variants in C4B

This is a list of pathogenic ClinVar variants found in the C4B region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-32017141-C-A		not specified	Benign (-)
6-32026995-C-G		not specified	Uncertain significance (Oct 05, 2022)
6-32027012-C-T		not specified	Uncertain significance (Jul 08, 2022)
6-32027032-C-G		not specified	Uncertain significance (Sep 07, 2022)
6-32027033-C-G		not specified	Uncertain significance (Nov 12, 2021)
6-32027043-G-A		not specified	Uncertain significance (Apr 25, 2022)
6-32027043-G-T		not specified	Uncertain significance (Dec 20, 2023)
6-32027051-A-G		not specified	Likely benign (Jan 04, 2024)
6-32027085-G-A		not specified	Uncertain significance (Aug 08, 2023)
6-32027332-G-C		not specified	Uncertain significance (Dec 06, 2021)
6-32027362-A-G		not specified	Benign/Likely benign (-)
6-32027369-T-C		not specified	Uncertain significance (Dec 14, 2023)
6-32027390-G-A		not specified	Uncertain significance (May 04, 2022)
6-32028502-C-T		not specified	Uncertain significance (Jul 15, 2021)
6-32028747-C-A		not specified	Benign (Jan 24, 2024)
6-32028766-G-A		not specified	Uncertain significance (Oct 12, 2021)
6-32028996-A-G		not specified	Uncertain significance (Jun 28, 2022)
6-32028999-G-A		Complement component 4b deficiency	Uncertain significance (Mar 26, 2018)
6-32029189-G-A		not specified	Benign (Jan 24, 2024)
6-32029221-C-T		not specified	Uncertain significance (Jul 20, 2022)
6-32029296-G-A		not specified	Uncertain significance (Jan 03, 2024)
6-32029339-G-A		Complement component 4b deficiency	Likely pathogenic (Jan 12, 2021)
6-32029581-G-GCT			Benign (Aug 01, 2023)
6-32029623-C-T		not specified	Likely benign (Feb 28, 2024)
6-32029631-C-T		not specified	Uncertain significance (Jun 28, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
C4B	protein_coding	protein_coding	ENST00000435363	41	20657

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.835	0.165	123351	0	9	123360	0.0000365

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.02	140	225	0.622	0.0000128	11186
Missense in Polyphen		50	76.079	0.65721		3093
Synonymous	2.91	61	97.6	0.625	0.00000594	3602
Loss of Function	3.41	3	19.1	0.157	8.50e-7	1023

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000250	0.000242
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000547	0.0000546
Finnish	0.00	0.00
European (Non-Finnish)	0.0000189	0.0000182
Middle Eastern	0.0000547	0.0000546
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
• Disease: DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:10092831, ECO:0000269|PubMed:17503323}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE.; DISEASE: Complement component 4B deficiency (C4BD) [MIM:614379]: A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis. {ECO:0000269|PubMed:3265961}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: 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;Dengue-2 Interactions with Complement and Coagulation Cascades;Oxidative Damage;Complement Activation;Complement and Coagulation Cascades;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;Activation of C3 and C5;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Initial triggering of complement;Regulation of Complement cascade;Complement cascade (Consensus)

Haploinsufficiency Scores

• pHI: 0.277
• ghis: 0.458

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: C4b
• Phenotype: immune system phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: proteolysis;inflammatory response;complement activation;complement activation, classical pathway;opsonization;negative regulation of endopeptidase activity;regulation of complement activation;detection of molecule of bacterial origin;innate immune response;positive regulation of apoptotic cell clearance
• Cellular component: extracellular region;extracellular space;plasma membrane;cell junction;axon;dendrite;other organism cell;synapse;extracellular exosome;blood microparticle
• Molecular function: complement binding;serine-type endopeptidase activity;endopeptidase inhibitor activity;carbohydrate binding