CIT

protein-coding

citron rho-interacting serine/threonine kinase, the group of AGC family kinases|MicroRNA protein coding host genes

Gene summary

This gene encodes a serine/threonine-protein kinase that functions in cell division. Together with the kinesin KIF14, this protein localizes to the central spindle and midbody, and functions to promote efficient cytokinesis. This protein is involved in central nervous system development. Polymorphisms in this gene are associated with bipolar disorder and risk for schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

MANE transcript

NM_001206999.2

Inheritance

ClinVar variants

P:25U:324B:171

Top phenotype

Microcephaly 17, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr12:119,685,791-119,877,320

External References & Databases

Ensembl (ENSG00000122966)

Transcript & Mutation Effects

hg38 • Region Span ~191.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 17, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014908

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly 17, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014908

Submitter: Ambry Genetics

microcephaly 17, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014908

Submitter: G2P

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly 17, primary, autosomal recessiveAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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: 27453578; 27453579; 27503289; 27519304

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CIT variants in ClinVar

10 Conditions Cataloged

not providedTotal: 404

Inborn genetic diseasesTotal: 236

not specifiedTotal: 61

CIT-related disorderTotal: 55

Microcephaly 17, primary, autosomal recessiveTotal: 46

Autosomal recessive primary microcephalyTotal: 4

Long QT syndromeTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001206999.2. 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			8 clinvar	133 clinvar	10 clinvar	151
missense	4 clinvar	2 clinvar	304 clinvar	26 clinvar	2 clinvar	338
nonsense	6 clinvar	2 clinvar	3 clinvar			11
start loss						0
frameshift	4 clinvar	2 clinvar				6
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	9 clinvar			14
Total	16	9	324	159	12	520

Highest pathogenic variant AF is 0.000024279158

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001206999.2	RefSeq	NP_001193928.1	47	MANE Select
ENST00000392521.7	Ensembl	ENSP00000376306.2	47	MANE Select
NM_007174.3	RefSeq	NP_009105.1	46	Standard
ENST00000261833.11	Ensembl	ENSP00000261833.7	46	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

G13 Signaling Pathway
Signal Transduction
RHO GTPases activate CIT
RHO GTPase Effectors
Signaling by Rho GTPases

Biological Process

G2/M transition of mitotic cell cycle
mitotic cell cycle
mitotic cytokinesis
protein phosphorylation
Golgi organization

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding
Rho GTPase binding
SH3 domain binding

Cellular Component

cytosol
membrane
midbody
Golgi cisterna
cleavage furrow

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392521
Coding exons: 47
Length: 191501
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125747
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.82	825	1.20e+3	0.689	0.0000743	13576
Missense (PolyPhen)		234	381.37	0.61358		4263
Synonymous	1.10	442	472	0.936	0.0000301	3901
Loss of Function	8.44	23	125	0.185	0.00000699	1397

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00027	0.00025	rare
South Asian	0.00017	0.00016	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in cytokinesis. Required for KIF14 localization to the central spindle and midbody. Putative RHO/RAC effector that binds to the GTP-bound forms of RHO and RAC1. It probably binds p21 with a tighter specificity in vivo. Displays serine/threonine protein kinase activity. Plays an important role in the regulation of cytokinesis and the development of the central nervous system. Phosphorylates MYL9/MLC2. {ECO:0000269|PubMed:16236794, ECO:0000269|PubMed:16431929, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:27453578}.;
Disease: DISEASE: Microcephaly 17, primary, autosomal recessive (MCPH17) [MIM:617090]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH17 is a severe form characterized by lissencephaly, enlarged ventricles, agenesis of the corpus callosum, cerebellar hypoplasia, and brainstem hypoplasia. Patients manifest delayed psychomotor development, intellectual disability, spasticity, axial hypotonia, and dysmorphic features. {ECO:0000269|PubMed:27453578, ECO:0000269|PubMed:27453579, ECO:0000269|PubMed:27503289, ECO:0000269|PubMed:27519304}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.371

Intolerance Scores

LoFtool: 0.475
RVIS EVS: -2.35
RVIS percentile EVS: 1.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.858

Gene Damage Prediction

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