C1S

complement C1s, the group of Sushi domain containing|Complement system activation components

Basic information

Region (hg38): 12:6988258-7071032

Links

ENSG00000182326 ∙ NCBI:716 ∙ OMIM:120580 ∙ HGNC:1247 ∙ Uniprot:P09871 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Ehlers-Danlos syndrome, periodontal type 1 (Moderate), mode of inheritance: AD
• Ehlers-Danlos syndrome, periodontal type 2 (Strong), mode of inheritance: AD
• complement component C1s deficiency (Strong), mode of inheritance: AR
• Ehlers-Danlos syndrome, periodontal type 2 (Limited), mode of inheritance: AD
• Ehlers-Danlos syndrome, periodontitis type (Supportive), mode of inheritance: AD
• complement component C1s deficiency (Strong), mode of inheritance: AR
• Ehlers-Danlos syndrome, periodontal type 2 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ehlers-Danlos syndrome, periodontal type 2; Complement component C1s deficiency	AD/AR	Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Oncologic	Ehlers-Danlos syndrome, periodontal type has been described as inolving risk of arterial and gastrointestinal rupture as well as recurrent infections, and awareness may allow prompt diagnosis and management; Individuals with Ehlers-Danlos syndrome, periodontal have been described with Wilms tumor (as well as other types of neoplasms), and awareness may allow early detection and treatment; Individuals with Complement component C1s deficiency may suffer from conditions such as severe infections, for which prophylaxis and/or early and aggressive treatment of infection may be beneficial; Immunosuppression may be beneficial for autoimmune phenomena (such as lupus nephritis)	Allergy/Immunology/Infectious; Dental; Dermatologic; Musculoskeletal; Oncologic; Renal	9856483; 9973493; 11390518; 19155518; 20191570; 27745832

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the C1S gene.

• not provided (340 variants)
• Inborn genetic diseases (20 variants)
• Ehlers-Danlos syndrome, periodontal type 2 (8 variants)
• not specified (6 variants)
• Ehlers-Danlos syndrome, periodontal type 2;Complement component C1s deficiency (5 variants)
• Complement component C1s deficiency;Ehlers-Danlos syndrome, periodontal type 2 (4 variants)
• Complement component C1s deficiency (4 variants)
• Ehlers-Danlos syndrome, periodontal type 1 (2 variants)
• C1S-related condition (2 variants)
• Hereditary angioedema with normal C1Inh (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the C1S 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				77	5	82
missense	1		166	6	3	176
nonsense	1		6			7
start loss						0
frameshift	4	1	8			13
inframe indel	1		1			2
splice donor/acceptor (+/-2bp)			2			2
splice region			4	2	4	10
non coding			7	28	20	55
Total	7	1	190	111	28

Variants in C1S

This is a list of pathogenic ClinVar variants found in the C1S region.

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

Position	Type	Phenotype	Significance	ClinVar
12-7018351-T-C		not specified	Uncertain significance (Sep 01, 2021)
12-7018373-C-A		not specified	Uncertain significance (Oct 27, 2022)
12-7018381-A-G		not specified	Uncertain significance (Apr 07, 2023)
12-7018412-C-T		not specified	Uncertain significance (Jul 14, 2021)
12-7061914-T-C		Ehlers-Danlos syndrome, periodontal type 2	Likely pathogenic (Nov 24, 2023)
12-7061922-G-A			Uncertain significance (Dec 20, 2022)
12-7061925-A-G			Likely benign (Jan 25, 2024)
12-7061930-G-A			Likely benign (Nov 15, 2022)
12-7062058-C-T			Benign (May 10, 2021)
12-7062107-T-TA			Benign (Jun 04, 2021)
12-7062270-C-CAAAAA			Benign (Jun 19, 2021)
12-7062357-C-T			Benign (May 10, 2021)
12-7062455-C-T			Likely benign (Dec 11, 2023)
12-7062463-CTG-C			Likely benign (Nov 25, 2022)
12-7062477-G-T			Uncertain significance (Sep 01, 2022)
12-7062494-C-T			Uncertain significance (Jan 25, 2024)
12-7062500-G-T			Likely benign (Dec 07, 2019)
12-7062500-GC-TT			Uncertain significance (Jan 14, 2024)
12-7062501-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Feb 27, 2024)
12-7062503-T-C		Hereditary angioedema with normal C1Inh	not provided (Feb 01, 2020)
12-7062506-G-T			Uncertain significance (Jan 25, 2023)
12-7062509-T-C			Uncertain significance (Dec 20, 2022)
12-7062516-A-T		Inborn genetic diseases	Uncertain significance (Dec 27, 2023)
12-7062517-G-A			Likely benign (Feb 10, 2022)
12-7062523-C-A			Likely benign (Sep 14, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
C1S	protein_coding	protein_coding	ENST00000406697	11	81986

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000677	0.999	125722	0	26	125748	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.559	342	372	0.918	0.0000206	4527
Missense in Polyphen		100	136.19	0.73429		1735
Synonymous	-0.392	144	138	1.04	0.00000779	1318
Loss of Function	3.28	11	30.5	0.360	0.00000164	381

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000337	0.000337
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000123	0.000123
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4.
• Disease: DISEASE: Complement component C1s deficiency (C1SD) [MIM:613783]: A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. {ECO:0000269|PubMed:11390518}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ehlers-Danlos syndrome, periodontal type, 2 (EDSPD2) [MIM:617174]: A form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSPD2 is characterized by the association of typical features of Ehlers-Danlos syndrome with gingival recession and severe early- onset periodontal disease, leading to premature loss of permanent teeth. EDSPD2 transmission pattern is consistent with autosomal dominant inheritance. {ECO:0000269|PubMed:27745832}. 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);Human Complement System;Dengue-2 Interactions with Complement and Coagulation Cascades;Oxidative Damage;Complement Activation;Complement and Coagulation Cascades;classical complement pathway;Innate Immune System;Immune System;Initial triggering of complement;Classical antibody-mediated complement activation;Regulation of Complement cascade;Creation of C4 and C2 activators;Complement cascade (Consensus)

Recessive Scores

• pRec: 0.443

Intolerance Scores

• loftool: 0.189
• rvis_EVS: -0.04
• rvis_percentile_EVS: 50.45

Haploinsufficiency Scores

• pHI: 0.190
• hipred: N
• hipred_score: 0.222
• ghis: 0.526

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.935

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: C1s2

Gene ontology

• Biological process: proteolysis;complement activation;complement activation, classical pathway;regulation of complement activation;innate immune response
• Cellular component: extracellular region;extracellular space;blood microparticle
• Molecular function: serine-type endopeptidase activity;calcium ion binding;protein binding;identical protein binding