GeneBe

ZIC2

protein-coding

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

Gene summary

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This protein functions as a transcriptional repressor and may regulate tissue specific expression of dopamine receptor D1. Expansion of an alanine repeat in the C-terminus of the encoded protein and other mutations in this gene cause holoprosencephaly type 5. Holoprosencephaly is the most common structural anomaly of the human brain. A polyhistidine tract polymorphism in this gene may be associated with increased risk of neural tube defects. This gene is closely linked to a gene encoding zinc finger protein of the cerebellum 5, a related family member on chromosome 13. [provided by RefSeq, Jul 2016]

MANE transcript

NM_007129.5

Inheritance

AD

ClinVar variants

P:56U:232B:170

Top phenotype

Holoprosencephaly 5

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr13:99,981,784-99,986,765

External References & Databases

Ensembl (ENSG00000043355)NCBI Gene (7546)OMIM (603073)HGNC:12873GenCCUniProt (O95409)AlphaFoldClinVar (ZIC2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

holoprosencephaly 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012322

Submitter: Genomics England PanelApp

holoprosencephaly 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012322

Submitter: G2P

holoprosencephaly 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012322

Submitter: PanelApp Australia

holoprosencephaly 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012322

Submitter: Labcorp Genetics (formerly Invitae)

holoprosencephaly 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012322

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Holoprosencephaly 5AD

Manifestation: Endocrine; Neurologic

Intervention: General

Rationale: 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

Refs: 9771712; 11285244; 19955556; 20104608Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZIC2 variants in ClinVar

10 Conditions Cataloged
Holoprosencephaly 5Total: 398
not providedTotal: 99
Inborn genetic diseasesTotal: 77
ZIC2-related disorderTotal: 42
not specifiedTotal: 39
Fetal anomalies with a likely genetic causeTotal: 3
Abnormality of the nervous systemTotal: 1
Holoprosencephaly sequenceTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007129.5. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
154
clinvar
6
clinvar
 163
missense
3
clinvar
12
clinvar
224
clinvar
7
clinvar
 246
nonsense
5
clinvar
3
clinvar
 8
start loss
2
clinvar
 2
frameshift
22
clinvar
9
clinvar
3
clinvar
3
clinvar
 37
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
 2
Total31252321646458

Highest pathogenic variant AF is 7.934241e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_007129.5RefSeqNP_009060.23MANE Select
ENST00000376335.8EnsemblENSP00000365514.33MANE Select
ENST00001069163.1EnsemblENSP00000738969.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
zic2bDanio rerio

Structure: melanoblast

Quality: aggregated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Mesodermal Commitment Pathway
  • Glucocorticoid Receptor Pathway
  • Nuclear Receptors Meta-Pathway

Biological Process

  • central nervous system development
  • brain development
  • visual perception
  • cell differentiation
  • negative regulation of transcription, DNA-templated

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

Cellular Component

  • nucleus
  • cytoplasm
  • nuclear body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000376335
Coding exons
3
Length
4993
Individuals with no LoFs
114911
Homozygous LoFs
0
Heterozygous LoFs
96
Defined
115007
p
0.000417
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.21982370.4130.00001123435
Missense (PolyPhen)2991.1040.318321286
Synonymous-2.951381001.370.000005271072
Loss of Function3.10011.20.004.87e-7142

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0120.0061notable
European (Non-Finnish)0.000380.00019rare
South Asian00.0absent
Other0.00170.00086notable

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.230

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.815

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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