ACAN

aggrecan, the group of V-set domain containing|Sushi domain containing|Hyalectan proteoglycans|C-type lectin domain containing

Basic information

Region (hg38): 15:88803436-88875353

Previous symbols: [ "MSK16", "CSPG1", "AGC1" ]

Links

ENSG00000157766 ∙ NCBI:176 ∙ OMIM:155760 ∙ HGNC:319 ∙ Uniprot:P16112 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spondyloepiphyseal dysplasia, Kimberley type (Definitive), mode of inheritance: AD
• spondyloepimetaphyseal dysplasia, aggrecan type (Definitive), mode of inheritance: AR
• spondyloepiphyseal dysplasia, Kimberley type (Supportive), mode of inheritance: AD
• spondyloepimetaphyseal dysplasia, aggrecan type (Supportive), mode of inheritance: AR
• osteochondritis dissecans (Supportive), mode of inheritance: AD
• short stature-advanced bone age-early-onset osteoarthritis syndrome (Supportive), mode of inheritance: AD
• spondyloepimetaphyseal dysplasia, aggrecan type (Strong), mode of inheritance: AR
• osteochondritis dissecans (Definitive), mode of inheritance: AD
• spondyloepiphyseal dysplasia, Kimberley type (Limited), mode of inheritance: AD
• spondyloepimetaphyseal dysplasia, aggrecan type (Limited), mode of inheritance: AR
• short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (Definitive), mode of inheritance: AD
• spondyloepiphyseal dysplasia, Kimberley type (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spondyloepimetaphyseal dysplasia, aggrecan type; Spondyloepiphyseal dysplasia, Kimberley type; Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans	AD	Endocrine	Individuals have been described as benefiting from growth hormone treatment	Craniofacial; Endocrine; Musculoskeletal	14353963; 14216462; 7331787; 3968094; 1978986; 16080123; 18226555; 19110214; 20137779; 27710243; 28331218; 30124491

ClinVar

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

• not_provided (1010 variants)
• Inborn_genetic_diseases (382 variants)
• Short_stature_and_advanced_bone_age,_with_or_without_early-onset_osteoarthritis_and/or_osteochondritis_dissecans (95 variants)
• not_specified (93 variants)
• Spondyloepimetaphyseal_dysplasia,_aggrecan_type (54 variants)
• Spondyloepiphyseal_dysplasia,_Kimberley_type (45 variants)
• Osteochondritis_dissecans (38 variants)
• ACAN-related_disorder (38 variants)
• Meniere_disease (5 variants)
• Short_stature_and_advanced_bone_age,_with_early-onset_osteoarthritis (4 variants)
• Short_stature_and_advanced_bone_age (4 variants)
• Spondyloepiphyseal_dysplasia (2 variants)
• See_cases (2 variants)
• Short_stature-advanced_bone_age-early-onset_osteoarthritis_syndrome (1 variants)
• Short_stature (1 variants)
• Skeletal_dysplasia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACAN gene is commonly pathogenic or not. These statistics are base on transcript: NM_001369268.1. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	13	211	28	253
missense	5	11	731	68	22	837
nonsense	42	21				63
start loss		1	1			2
frameshift	54	31	2			87
splice donor/acceptor (+/-2bp)	3	14	3			20
Total	104	79	750	279	50

Highest pathogenic variant AF is 0.000281592

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACAN	protein_coding	protein_coding	ENST00000439576	17	71912

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.11e-7	124951	0	13	124964	0.0000520

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.207	1197	1.22e+3	0.983	0.0000717	15847
Missense in Polyphen		323	330.93	0.97605		4398
Synonymous	0.294	498	506	0.983	0.0000325	5615
Loss of Function	7.08	7	71.7	0.0976	0.00000354	981

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000193	0.000191
Ashkenazi Jewish	0.0000994	0.0000993
East Asian	0.000223	0.000166
Finnish	0.00	0.00
European (Non-Finnish)	0.0000355	0.0000353
Middle Eastern	0.000223	0.000166
South Asian	0.0000654	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This proteoglycan is a major component of extracellular matrix of cartilagenous tissues. A major function of this protein is to resist compression in cartilage. It binds avidly to hyaluronic acid via an N-terminal globular region.
• Disease: DISEASE: Spondyloepiphyseal dysplasia type Kimberley (SEDK) [MIM:608361]: Spondyloepiphyseal dysplasias are a heterogeneous group of congenital chondrodysplasias that specifically affect epiphyses and vertebrae. The autosomal dominant SEDK is associated with premature degenerative arthropathy. {ECO:0000269|PubMed:16080123}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondyloepimetaphyseal dysplasia, aggrecan type (SEMDAG) [MIM:612813]: A bone disease characterized by severe short stature, macrocephaly, severe midface hypoplasia, short neck, barrel chest and brachydactyly. The radiological findings comprise long bones with generalized irregular epiphyses with widened metaphyses, especially at the knees, platyspondyly, and multiple cervical-vertebral clefts. {ECO:0000269|PubMed:19110214}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) [MIM:165800]: An autosomal dominant disease characterized by short stature, advanced bone maturation, early-onset osteoarthritis, and mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disk disease and osteochondritis dissecans. Osteochondritis dissecans is defined as a separation of cartilage and subchondral bone from the surrounding tissue. {ECO:0000269|PubMed:20137779}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Spinal Cord Injury;Endochondral Ossification;Metabolism of carbohydrates;Keratan sulfate biosynthesis;Keratan sulfate/keratin metabolism;Glycosaminoglycan metabolism;Extracellular matrix organization;Metabolism;Integrin;Degradation of the extracellular matrix;ECM proteoglycans (Consensus)

Recessive Scores

• pRec: 0.570

Intolerance Scores

• loftool: 0.0378
• rvis_EVS: 1.28
• rvis_percentile_EVS: 93.77

Haploinsufficiency Scores

• pHI: 0.341
• hipred: N
• hipred_score: 0.481
• ghis: 0.423

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.555

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Acan
• Phenotype: growth/size/body region phenotype; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; normal phenotype; 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); 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); neoplasm; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: acana
• Affected structure: atrium
• Phenotype tag: abnormal
• Phenotype quality: increased size

Gene ontology

• Biological process: skeletal system development;cartilage condensation;chondrocyte development;proteolysis;cell adhesion;central nervous system development;heart development;keratan sulfate biosynthetic process;proteoglycan biosynthetic process;extracellular matrix organization;collagen fibril organization;keratan sulfate catabolic process
• Cellular component: extracellular region;basement membrane;Golgi lumen;extracellular matrix;lysosomal lumen;collagen-containing extracellular matrix;perisynaptic extracellular matrix;glutamatergic synapse;GABA-ergic synapse
• Molecular function: extracellular matrix structural constituent;protein binding;hyaluronic acid binding;extracellular matrix structural constituent conferring compression resistance;carbohydrate binding;metal ion binding