CILP

protein-coding

cartilage intermediate layer protein, the group of Immunoglobulin like domain containing

Gene summary

Major alterations in the composition of the cartilage extracellular matrix occur in joint disease, such as osteoarthrosis. This gene encodes the cartilage intermediate layer protein (CILP), which increases in early osteoarthrosis cartilage. The encoded protein was thought to encode a protein precursor for two different proteins; an N-terminal CILP and a C-terminal homolog of NTPPHase, however, later studies identified no nucleotide pyrophosphatase phosphodiesterase (NPP) activity. The full-length and the N-terminal domain of this protein was shown to function as an IGF-1 antagonist. An allelic variant of this gene has been associated with lumbar disc disease. [provided by RefSeq, Sep 2010]

MANE transcript

NM_003613.4

Inheritance

—

ClinVar variants

U:218B:18

Top phenotype

CILP-related disorder

gnomAD constraint

pLI —, LoF o/e 0.99

Max pathogenic AF

—

Genomic locus

chr15:65,194,760-65,211,473

External References & Databases

Ensembl (ENSG00000138615)

Transcript & Mutation Effects

hg38 • Region Span ~16.7 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 CILP variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 222

CILP-related disorderTotal: 7

not providedTotal: 6

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003613.4. 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				6 clinvar	1 clinvar	7
missense			217 clinvar	8 clinvar	3 clinvar	228
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	218	14	4	236

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003613.4	RefSeq	NP_003604.4	8	MANE Select
ENST00000261883.6	Ensembl	ENSP00000261883.4	8	MANE Select
ENST00000888802.1	Ensembl	ENSP00000558861.1	8	Standard
ENST00000888802.2	Ensembl	ENSP00000558861.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Signaling by Receptor Tyrosine Kinases
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)

Biological Process

negative regulation of gene expression
dephosphorylation
negative regulation of insulin-like growth factor receptor signaling pathway
negative regulation of SMAD protein signal transduction
cellular response to transforming growth factor beta stimulus

Molecular Function

alkaline phosphatase activity
nucleotide diphosphatase activity
extracellular matrix structural constituent

Cellular Component

extracellular space
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261883
Coding exons: 8
Length: 15490
Individuals with no LoFs: 125492
Homozygous LoFs: 3
Heterozygous LoFs: 253
Defined: 125748
p: 0.00102

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.170	693	706	0.982	0.0000418	7772
Missense (PolyPhen)		332	339.52	0.97786		3706
Synonymous	0.573	258	270	0.956	0.0000147	2404
Loss of Function	0.0626	39	39.4	0.989	0.00000215	451

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0016	notable
Latino/Admixed American	0.00095	0.00095	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0019	0.0018	notable
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00080	0.00078	rare
South Asian	0.0018	0.0017	notable
Other	0.0021	0.0021	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably plays a role in cartilage scaffolding. May act by antagonizing TGF-beta1 (TGFB1) and IGF1 functions. Has the ability to suppress IGF1-induced proliferation and sulfated proteoglycan synthesis, and inhibits ligand-induced IGF1R autophosphorylation. May inhibit TGFB1-mediated induction of cartilage matrix genes via its interaction with TGFB1. Overexpression may lead to impair chondrocyte growth and matrix repair and indirectly promote inorganic pyrophosphate (PPi) supersaturation in aging and osteoarthritis cartilage. {ECO:0000269|PubMed:12746903, ECO:0000269|PubMed:15864306}.;
Disease: DISEASE: Intervertebral disc disease (IDD) [MIM:603932]: A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. {ECO:0000269|PubMed:15864306}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. {ECO:0000269|PubMed:15864306}.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.980
RVIS EVS: -1.53
RVIS percentile EVS: 3.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.376

Gene Damage Prediction

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