S100A8

protein-coding

S100 calcium binding protein A8, the group of S100 calcium binding proteins|EF-hand domain containing

Gene summary

The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition of casein kinase and as a cytokine. Altered expression of this protein is associated with the disease cystic fibrosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

Previous symbols:

CAGA
CFAG

MANE transcript

NM_002964.5

Inheritance

—

ClinVar variants

U:7B:2

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr1:153,390,032-153,391,073

External References & Databases

Ensembl (ENSG00000143546)

Transcript & Mutation Effects

hg38 • Region Span ~1.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to S100A8 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002964.5. 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						0
missense			7 clinvar	2 clinvar		9
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	7	2	0	9

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002964.5	RefSeq	NP_002955.2	2	MANE Select
ENST00000368733.4	Ensembl	ENSP00000357722.3	2	MANE Select
NM_001319196.1	RefSeq	NP_001306125.1	3	Standard
NM_001319197.1	RefSeq	NP_001306126.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

IL-17 signaling pathway - Homo sapiens (human)
Vitamin D Receptor Pathway
Neutrophil degranulation
Toll-Like Receptors Cascades
Antimicrobial peptides

Biological Process

cytokine production
toll-like receptor signaling pathway
leukocyte migration involved in inflammatory response
acute inflammatory response
chronic inflammatory response

Molecular Function

calcium ion binding
protein binding
microtubule binding
zinc ion binding
Toll-like receptor 4 binding

Cellular Component

extracellular region
extracellular space
nucleus
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368733
Coding exons: 2
Length: 1157
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125672
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0401	51	51.8	0.984	0.00000272	626
Missense (PolyPhen)		12	15.795	0.75972		206
Synonymous	-0.0138	23	22.9	1.00	0.00000149	159
Loss of Function	0.582	1	1.86	0.539	7.74e-8	25

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH- oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF- kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity. {ECO:0000269|PubMed:12626582, ECO:0000269|PubMed:15331440, ECO:0000269|PubMed:15598812, ECO:0000269|PubMed:15642721, ECO:0000269|PubMed:16258195, ECO:0000269|PubMed:19087201, ECO:0000269|PubMed:19122197, ECO:0000269|PubMed:19935772, ECO:0000269|PubMed:21487906, ECO:0000269|PubMed:22363402, ECO:0000269|PubMed:22808130, ECO:0000269|PubMed:25417112}.;

Recessive Scores

pRec: 0.455

Intolerance Scores

RVIS EVS: 0.04
RVIS percentile EVS: 56.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.898

Gene Damage Prediction

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