C6

protein-coding

complement C6, the group of Sushi domain containing|Complement system activation components

Gene summary

This gene encodes a component of the complement cascade. The encoded protein is part of the membrane attack complex that can be incorporated into the cell membrane and cause cell lysis. Mutations in this gene are associated with complement component-6 deficiency. Transcript variants encoding the same protein have been described.[provided by RefSeq, Nov 2012]

MANE transcript

NM_000065.5

Inheritance

ClinVar variants

P:72U:292B:179

Top phenotype

Complement component 6 deficiency

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr5:41,142,116-41,261,438

External References & Databases

Ensembl (ENSG00000039537)

Transcript & Mutation Effects

hg38 • Region Span ~119.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complement component 6 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012908

Submitter: Labcorp Genetics (formerly Invitae)

complement component 6 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012908

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Complement component 6 deficiencyAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis (including related to specific immunization) and early and aggressive treatment of infections may be beneficial

Comments: Antiinfectious prophylaxis (including related to specific immunization strategies) and early and aggressive treatment of infections may be beneficial

Refs: 11344568; 11344569; 6835295; 8690922; 17257682; 17893986; 21270745; 22123893; 22288589; 22668955

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C6 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 528

Inborn genetic diseasesTotal: 147

not specifiedTotal: 48

Complement component 6 deficiencyTotal: 38

C6-related disorderTotal: 31

C6-related disordersTotal: 8

Primary ciliary dyskinesiaTotal: 1

C6 deficiency, subtotalTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000065.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	2 clinvar	148 clinvar	1 clinvar	152
missense			289 clinvar	24 clinvar	6 clinvar	319
nonsense	15 clinvar	11 clinvar				26
start loss			1 clinvar			1
frameshift	17 clinvar	15 clinvar				32
splice donor/acceptor (+/-2bp)		13 clinvar				13
Total	32	40	292	172	7	543

Highest pathogenic variant AF is 0.0028107413

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 120 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000065.5	RefSeq	NP_000056.2	17	MANE Select
ENST00000337836.10	Ensembl	ENSP00000338861.5	17	MANE Select
NM_001115131.4	RefSeq	NP_001108603.2	17	Standard
ENST00000263413.7	Ensembl	ENSP00000263413.3	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prion diseases - Homo sapiens (human)
Complement and coagulation cascades - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)
Allograft Rejection
Human Complement System

Biological Process

in utero embryonic development
positive regulation of activation of membrane attack complex
complement activation
complement activation, classical pathway
cytolysis

Molecular Function

protein binding

Cellular Component

extracellular region
membrane attack complex
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263413
Coding exons: 17
Length: 119205
Individuals with no LoFs: 124585
Homozygous LoFs: 4
Heterozygous LoFs: 1153
Defined: 125742
p: 0.00461

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.877	535	481	1.11	0.0000249	6128
Missense (PolyPhen)		165	167.1	0.98744		2112
Synonymous	-2.83	221	174	1.27	0.00000900	1696
Loss of Function	1.59	40	52.5	0.763	0.00000287	637

Population LoF Frequency

Population	CAF	p-value	Status
African	0.020	0.020	notable
Latino/Admixed American	0.0029	0.0029	notable
Ashkenazi Jewish	0.0020	0.0020	notable
East Asian	0.0026	0.0026	notable
Finnish	0.0016	0.0016	notable
European (Non-Finnish)	0.0043	0.0043	notable
South Asian	0.0039	0.0039	notable
Other	0.0049	0.0049	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells.;
Disease: DISEASE: Complement component 6 deficiency (C6D) [MIM:612446]: A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. {ECO:0000269|PubMed:15565285}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.273
RVIS EVS: 1.32
RVIS percentile EVS: 94.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.547

Gene Damage Prediction

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