ZIC2

Zic family member 2, the group of Zinc fingers C2H2-type

Basic information

Region (hg38): 13:99981783-99986765

Links

ENSG00000043355 ∙ NCBI:7546 ∙ OMIM:603073 ∙ HGNC:12873 ∙ Uniprot:O95409 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• holoprosencephaly 5 (Definitive), mode of inheritance: AD
• holoprosencephaly 5 (Strong), mode of inheritance: AD
• holoprosencephaly 5 (Strong), mode of inheritance: AD
• holoprosencephaly (Supportive), mode of inheritance: AR
• holoprosencephaly 5 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holoprosencephaly 5	AD	General	Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Endocrine; Neurologic	9771712; 11285244; 19955556; 20104608

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZIC2 gene.

• Holoprosencephaly 5 (219 variants)
• not provided (51 variants)
• Inborn genetic diseases (18 variants)
• not specified (15 variants)
• ZIC2-related condition (5 variants)
• Abnormality of the nervous system (1 variants)
• Holoprosencephaly 1 (1 variants)
• Microcephaly;Holoprosencephaly sequence (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZIC2 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			1	74	8	83
missense	2	4	97	1		104
nonsense	3	1				4
start loss			1			1
frameshift	14	3				17
inframe indel	2	3	38	1	1	45
splice donor/acceptor (+/-2bp)	1	1				2
splice region			3	1		4
non coding			2	9	9	20
Total	22	12	139	85	18

Variants in ZIC2

This is a list of pathogenic ClinVar variants found in the ZIC2 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-99982046-G-C			Uncertain significance (Aug 04, 2017)
13-99982065-A-T		Holoprosencephaly 5	Uncertain significance (Dec 04, 2021)
13-99982066-T-C		Holoprosencephaly 5	Uncertain significance (Aug 17, 2023)
13-99982070-C-T		Holoprosencephaly 5	Likely benign (Oct 27, 2022)
13-99982078-C-T		Holoprosencephaly 5	Uncertain significance (Aug 16, 2022)
13-99982086-C-T			Likely pathogenic (Mar 18, 2019)
13-99982091-C-T		Holoprosencephaly 5	Likely benign (May 07, 2022)
13-99982101-G-C			Uncertain significance (Jul 19, 2017)
13-99982103-G-A			Likely benign (Apr 16, 2018)
13-99982105-T-C		Holoprosencephaly 5	Uncertain significance (Dec 02, 2021)
13-99982107-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
13-99982111-G-A		ZIC2-related disorder	Uncertain significance (Mar 12, 2023)
13-99982115-C-T		ZIC2-related disorder	Likely benign (May 01, 2019)
13-99982116-G-C		Holoprosencephaly 5	Uncertain significance (Jun 27, 2022)
13-99982118-G-T		Holoprosencephaly 5	Likely benign (Oct 19, 2022)
13-99982121-C-T		Holoprosencephaly 5	Likely benign (May 09, 2022)
13-99982139-CGCGGCGGCG-C		Holoprosencephaly 5	Uncertain significance (Jul 27, 2021)
13-99982139-C-CGCG		Holoprosencephaly 5	Uncertain significance (Jun 30, 2023)
13-99982141-C-G		Inborn genetic diseases • Holoprosencephaly 5	Uncertain significance (Oct 13, 2023)
13-99982144-C-T		Holoprosencephaly 5	Uncertain significance (Sep 04, 2023)
13-99982147-C-G		Inborn genetic diseases	Uncertain significance (Jun 11, 2021)
13-99982147-C-CGGGGGG		Inborn genetic diseases	Uncertain significance (Mar 24, 2021)
13-99982147-C-CGGGGGGGGG		Inborn genetic diseases	Uncertain significance (Jul 08, 2021)
13-99982147-C-CGGGGGGGGGG		Inborn genetic diseases	Pathogenic (Dec 15, 2021)
13-99982150-C-G		Inborn genetic diseases	Uncertain significance (Jul 08, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZIC2	protein_coding	protein_coding	ENST00000376335	3	4993

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.974	0.0263	114911	0	96	115007	0.000417

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.21	98	237	0.413	0.0000112	3435
Missense in Polyphen		29	91.104	0.31832		1286
Synonymous	-2.95	138	100	1.37	0.00000527	1072
Loss of Function	3.10	0	11.2	0.00	4.87e-7	142

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0121	0.00605
European (Non-Finnish)	0.000377	0.000188
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00172	0.000857

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a transcriptional activator or repressor. Plays important roles in the early stage of organogenesis of the CNS. Activates the transcription of the serotonin transporter SERT in uncrossed ipsilateral retinal ganglion cells (iRGCs) to refine eye-specific projections in primary visual targets. Its transcriptional activity is repressed by MDFIC. Involved in the formation of the ipsilateral retinal projection at the optic chiasm midline. Drives the expression of EPHB1 on ipsilaterally projecting growth cones. Binds to the minimal GLI-consensus sequence 5'-TGGGTGGTC-3'. Associates to the basal SERT promoter region from ventrotemporal retinal segments of retinal embryos.
• Disease: DISEASE: Holoprosencephaly 5 (HPE5) [MIM:609637]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. {ECO:0000269|PubMed:11285244, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15590697, ECO:0000269|PubMed:19177455, ECO:0000269|PubMed:9771712}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mesodermal Commitment Pathway;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway (Consensus)

Recessive Scores

• pRec: 0.230

Haploinsufficiency Scores

• pHI: 0.878
• ghis: 0.627

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.815

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Zic2
• Phenotype: vision/eye phenotype; digestive/alimentary 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); limbs/digits/tail phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; pigmentation phenotype; growth/size/body region phenotype; 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); 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); normal phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: zic2b
• Affected structure: melanoblast
• Phenotype tag: abnormal
• Phenotype quality: aggregated

Gene ontology

• Biological process: central nervous system development;brain development;visual perception;cell differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of DNA-binding transcription factor activity
• Cellular component: nucleus;cytoplasm;nuclear body
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;chromatin DNA binding;metal ion binding