CANT1

protein-coding

calcium activated nucleotidase 1

Gene summary

This protein encoded by this gene belongs to the apyrase family. It functions as a calcium-dependent nucleotidase with a preference for UDP. Mutations in this gene are associated with Desbuquois dysplasia with hand anomalies. Alternatively spliced transcript variants have been noted for this gene.[provided by RefSeq, Mar 2010]

MANE transcript

NM_001159773.2

Inheritance

ClinVar variants

P:54U:122B:182

Top phenotype

Desbuquois dysplasia 1

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr17:78,991,716-79,009,867

External References & Databases

Ensembl (ENSG00000171302)

Transcript & Mutation Effects

hg38 • Region Span ~18.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Desbuquois dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015426

Submitter: Orphanet

Desbuquois dysplasia 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009629

Submitter: ClinGen

*CANT1* was first reported in relation to autosomal recessive Desbuquois dysplasia 1 in 2009 (Huber et al., PMID: 19853239). Desbuquois dysplasia is a rare type of osteochondrodysplasia characterized by short stature with short extremities, severe joint laxity with dislocation, and fetal growth restriction. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern and phenotypic variability between Desbuquois dysplasia 1 and epiphyseal dysplasia, multiple, 7. Therefore, the disease entities have been lumped into one disease entity, Desbuquois dysplasia 1 (OMIM:251450). 7 frameshift, 6 missense, and 2 nonsense variants that have been reported in 13 probands in 6 publications (PMIDs: 19853239, 22539336, 25252066, 28229453, 28742282, 31988067) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is suspected loss of function (PMID: 32907608). This gene-disease relationship is also supported by functional alteration of patient cells and animal models (PMIDs: 19853239, 30439444, 32277574). In summary, there is definitive evidence supporting the relationship between *CANT1* and autosomal recessive Desbuquois dysplasia 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Prenatal GCEP on the meeting date September 10th, 2024 (SOP Version 11).

Desbuquois dysplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009629

Submitter: Labcorp Genetics (formerly Invitae)

Desbuquois dysplasia 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009629

Submitter: G2P

Clinical Genomic Database (CGD)

Desbuquois dysplasia 1AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Ophthalmologic

Rationale: As the condition can include glaucoma, appropriate surveillance may allow early detection and management

Refs: 1080993; 1959544; 7977470; 14679586; 14679587; 15211652; 19853239; 20358610; 20425819; 20358597; 21037275; 21412251; 21654728; 22539336

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CANT1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 319

Desbuquois dysplasia 1Total: 78

Inborn genetic diseasesTotal: 68

Epiphyseal dysplasia, multiple, 7Total: 23

not specifiedTotal: 18

CANT1-related disorderTotal: 13

Short statureTotal: 1

Multiple epiphyseal dysplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001159773.2. 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			3 clinvar	161 clinvar	1 clinvar	165
missense	4 clinvar	13 clinvar	115 clinvar	20 clinvar		152
nonsense	10 clinvar	5 clinvar				15
start loss						0
frameshift	14 clinvar	7 clinvar	2 clinvar			23
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	29	25	122	181	1	358

Highest pathogenic variant AF is 0.000047205955

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001159773.2	RefSeq	NP_001153245.1	3	MANE Select
ENST00000392446.10	Ensembl	ENSP00000376241.4	3	MANE Select
NM_001159772.2	RefSeq	NP_001153244.1	3	Standard
NM_138793.4	RefSeq	NP_620148.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Pyrimidine Metabolism
GLUT-1 deficiency syndrome
UMP Synthase Deiciency (Orotic Aciduria)

Biological Process

proteoglycan biosynthetic process
positive regulation of I-kappaB kinase/NF-kappaB signaling
neutrophil degranulation

Molecular Function

guanosine-diphosphatase activity
calcium ion binding
protein homodimerization activity
adenosine-diphosphatase activity
uridine-diphosphatase activity

Cellular Component

extracellular region
endoplasmic reticulum membrane
plasma membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302345
Coding exons: 3
Length: 18151
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 77
Defined: 125748
p: 0.000306

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.488	243	265	0.916	0.0000192	2594
Missense (PolyPhen)		72	87.406	0.82374		909
Synonymous	0.943	115	129	0.894	0.0000113	812
Loss of Function	0.760	10	13.0	0.772	6.33e-7	132

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00064	0.00064	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00015	0.00014	rare
European (Non-Finnish)	0.00037	0.00036	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-dependent nucleotidase with a preference for UDP. The order of activity with different substrates is UDP > GDP > UTP > GTP. Has very low activity towards ADP and even lower activity towards ATP. Does not hydrolyze AMP and GMP (PubMed:12234496, PubMed:15248776, PubMed:15006348, PubMed:16835225). Involved in proteoglycan synthesis (PubMed:22539336). {ECO:0000269|PubMed:12234496, ECO:0000269|PubMed:15006348, ECO:0000269|PubMed:15248776, ECO:0000269|PubMed:16835225, ECO:0000269|PubMed:22539336}.;
Disease: DISEASE: Desbuquois dysplasia 1 (DBQD1) [MIM:251450]: A chondrodysplasia characterized by severe prenatal and postnatal growth retardation (less than -5 SD), joint laxity, short extremities, progressive scoliosis, round face, midface hypoplasia, prominent bulging eyes. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advance carpal and tarsal bone age. Two forms of Desbuquois dysplasia are distinguished on the basis of the presence or absence of characteristic hand anomalies: an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and phalangeal dislocations. {ECO:0000269|PubMed:19853239, ECO:0000269|PubMed:20425819, ECO:0000269|PubMed:21037275, ECO:0000269|PubMed:21412251, ECO:0000269|PubMed:21654728, ECO:0000269|PubMed:22539336}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epiphyseal dysplasia, multiple, 7 (EDM7) [MIM:617719]: A form of multiple epiphyseal dysplasia, a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. EDM7 inheritance is autosomal recessive. {ECO:0000269|PubMed:28742282}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.0660
RVIS EVS: 0.02
RVIS percentile EVS: 55.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.108

Gene Damage Prediction

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