CAD

carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, the group of Glutamine amidotransferase class 1 domain containing

Basic information

Region (hg38): 2:27217369-27243943

Links

ENSG00000084774 ∙ NCBI:790 ∙ OMIM:114010 ∙ HGNC:1424 ∙ Uniprot:P27708 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 50 (Supportive), mode of inheritance: AR
• developmental and epileptic encephalopathy, 50 (Moderate), mode of inheritance: AR
• developmental and epileptic encephalopathy, 50 (Strong), mode of inheritance: AR
• developmental and epileptic encephalopathy, 50 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 50	AR	Biochemical; Gastrointestinal; Renal	Medical management (with uridine) has been described as beneficial; Among other manifestations, the conditions has been described as including renal tubular acidosis, which has been reported as amenable to treatment (eg, with citrate); The condition has been reported as including pan-disaccharidase deficiency, which was treated (with probiotics and digestive enzymes)	Biochemical; Gastrointestinal; Hematologic; Neurologic; Renal	25678555; 28007989

ClinVar

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

• not provided (49 variants)
• Developmental and epileptic encephalopathy, 50 (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CAD gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	715	16	741
missense		3	562	7	1	573
nonsense	21	1				22
start loss						0
frameshift	28	4	1			33
inframe indel			6			6
splice donor/acceptor (+/-2bp)	1	16	1	2	1	21
splice region		1	37	113	6	157
non coding			5	403	38	446
Total	50	24	585	1127	56

Highest pathogenic variant AF is 0.0000197

Variants in CAD

This is a list of pathogenic ClinVar variants found in the CAD region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-27217561-C-T			Likely benign (Jan 29, 2024)
2-27217563-A-G			Likely benign (Oct 04, 2021)
2-27217572-G-A			Likely benign (May 15, 2023)
2-27217575-C-T			Likely benign (Nov 30, 2022)
2-27217578-G-A			Likely benign (Nov 30, 2022)
2-27217578-G-T			Likely benign (Jun 05, 2023)
2-27217581-G-C			Likely benign (Jul 19, 2023)
2-27217584-C-G			Likely benign (Apr 03, 2023)
2-27217584-C-T			Likely benign (Aug 04, 2023)
2-27217594-C-G			Uncertain significance (Oct 18, 2022)
2-27217594-C-T			Uncertain significance (Sep 16, 2018)
2-27217595-A-G			Uncertain significance (Jul 19, 2022)
2-27217596-G-T			Uncertain significance (Nov 19, 2023)
2-27217597-C-G			Uncertain significance (Jun 03, 2022)
2-27217614-G-A			Likely benign (Jun 06, 2023)
2-27217623-C-T			Likely benign (Jun 10, 2023)
2-27217626-G-C			Likely benign (Dec 02, 2023)
2-27217629-A-G			Uncertain significance (Oct 03, 2023)
2-27217643-C-T			Likely benign (Jan 02, 2024)
2-27217644-C-A			Likely benign (May 13, 2023)
2-27217645-C-T			Likely benign (Jan 22, 2024)
2-27217652-G-A			Likely benign (Oct 26, 2023)
2-27217854-C-T			Benign (May 11, 2021)
2-27217858-C-G			Likely benign (Sep 27, 2023)
2-27217861-T-A			Likely benign (Dec 20, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CAD	protein_coding	protein_coding	ENST00000264705	44	26554

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000701	125714	0	34	125748	0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.34	913	1.36e+3	0.670	0.0000865	14317
Missense in Polyphen		289	572.9	0.50445		5999
Synonymous	-0.930	570	542	1.05	0.0000331	4754
Loss of Function	8.09	19	111	0.171	0.00000632	1170

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000341	0.000333
Ashkenazi Jewish	0.00	0.00
East Asian	0.000217	0.000217
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000159	0.000158
Middle Eastern	0.000217	0.000217
South Asian	0.0000658	0.0000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase). {ECO:0000269|PubMed:24332717}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 50 (EIEE50) [MIM:616457]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE50 is an autosomal recessive, progressive disease with onset in infancy and favorable response to treatment with oral uridine. {ECO:0000269|PubMed:25678555, ECO:0000269|PubMed:28087732}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Alanine, aspartate and glutamate metabolism - Homo sapiens (human);Pyrimidine metabolism - Homo sapiens (human);2-Hydroxyglutric Aciduria (D And L Form);Pyrimidine Metabolism;Hypoacetylaspartia;UMP Synthase Deiciency (Orotic Aciduria);Aspartate Metabolism;Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;MNGIE (Mitochondrial Neurogastrointestinal Encephalopathy);4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Glutamate Metabolism;Beta Ureidopropionase Deficiency;Canavan Disease;Dihydropyrimidinase Deficiency;Endothelin Pathways;Amino Acid metabolism;Pyrimidine metabolism;Metabolism of nucleotides;Alanine Aspartate Asparagine metabolism;Glutamate Glutamine metabolism;Pyrimidine biosynthesis;Metabolism;Nucleobase biosynthesis;UMP biosynthesis;superpathway of pyrimidine ribonucleotides <i>de novo</i> biosynthesis;Pyrimidine nucleotides nucleosides metabolism;superpathway of pyrimidine deoxyribonucleotides <i>de novo</i> biosynthesis;Validated targets of C-MYC transcriptional activation (Consensus)

Recessive Scores

• pRec: 0.132

Intolerance Scores

• rvis_EVS: -3.84
• rvis_percentile_EVS: 0.23

Haploinsufficiency Scores

• pHI: 0.667
• hipred: Y
• hipred_score: 0.706
• ghis: 0.648

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cad

Zebrafish Information Network

• Gene name: cad
• Affected structure: blood vessel endothelial cell
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: liver development;'de novo' pyrimidine nucleobase biosynthetic process;UTP biosynthetic process;glutamine metabolic process;nitrogen compound metabolic process;heart development;female pregnancy;lactation;response to amine;drug metabolic process;peptidyl-threonine phosphorylation;citrulline biosynthetic process;response to caffeine;animal organ regeneration;response to insulin;cellular response to drug;response to starvation;'de novo' UMP biosynthetic process;pyrimidine nucleoside biosynthetic process;protein autophosphorylation;cellular response to epidermal growth factor stimulus
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;membrane;nuclear matrix;protein-containing complex;cell projection;neuronal cell body;terminal bouton;extracellular exosome
• Molecular function: aspartate carbamoyltransferase activity;carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity;dihydroorotase activity;protein kinase activity;ATP binding;zinc ion binding;enzyme binding;identical protein binding;aspartate binding