CIC

protein-coding

capicua transcriptional repressor

Gene summary

The protein encoded by this gene is an ortholog of the Drosophila melanogaster capicua gene, and is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. This protein contains a conserved HMG domain that is involved in DNA binding and nuclear localization, and a conserved C-terminus. Studies suggest that the N-terminal region of this protein interacts with Atxn1 (GeneID:6310), to form a transcription repressor complex, and in vitro studies suggest that polyglutamine-expansion of ATXN1 may alter the repressor activity of this complex. Mutations in this gene have been associated with olidogdendrogliomas (PMID:21817013). In addition, translocation events resulting in gene fusions of this gene with both DUX4 (GeneID:100288687) and FOXO4 (GeneID:4303) have been associated with round cell sarcomas. There are multiple pseudogenes of this gene found on chromosomes 1, 4, 6, 7, 16, 20, and the Y chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

MANE transcript

NM_001386298.1

Inheritance

ClinVar variants

P:97U:602B:346

Top phenotype

Intellectual developmental disorder, autosomal dominant 45

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr19:42,268,537-42,295,797

External References & Databases

Ensembl (ENSG00000079432)

Transcript & Mutation Effects

hg38 • Region Span ~27.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 45STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030910

Submitter: G2P

intellectual developmental disorder, autosomal dominant 45DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030910

Submitter: Illumina

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 45STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030910

Submitter: Labcorp Genetics (formerly Invitae)

cerebral folate deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100034

Submitter: Franklin by Genoox

In a trio-based genetic analysis on patients with CFD and identified de-novo mutation in CIC. additioanly in a cohort of 48 CFD cases, 3 patients carried deleterious variants IN CIC http://dx.doi.org/10.1136/jmedgenet-2020-106987

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CIC* encodes capicua, a transcriptional repressor that plays a role in the development of the central nervous system. *CIC* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2017 (Lu et al., PMID: 28288114). The clinical features of affected individuals are variable and include developmental delay, intellectual disability, autism or autistic features, seizures and brain MRI abnormalities. Eight variants (4 frameshift, 2 nonsense, and 2 missense) that have been reported in eight probands in four publications (PMIDs: 21076407, 24307393, 28288114, 35165976) are included in this curation. Most variants are *de novo*. Two affected siblings likely inherited the variant from a parent with germline mosaicism, and in another proband the variant was inherited from an unaffected parent with low level mosaicism (PMID: 28288114). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *CIC* is highly constrained for truncating variants but not for missense variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including conditional mouse models (PMID: 28288114) and functional alterations in patient and non-patient cells (PMIDs: 32820034, 35165976). CIC binds to the promoter of folate transport genes, including *FOLR1*; loss-of-function variants in *CIC* downregulate FOLR1 expression, leading to cerebral folate deficiency (PMID: 32820034). In summary, there is definitive evidence supporting the relationship between *CIC* and autosomal dominant complex neurodevelopmental disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 45AD

Manifestation: 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: 28288114

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CIC variants in ClinVar

24 Conditions Cataloged

not providedTotal: 496

Inborn genetic diseasesTotal: 258

not specifiedTotal: 192

Intellectual developmental disorder, autosomal dominant 45Total: 174

CIC-related disorderTotal: 160

Intellectual disabilityTotal: 7

See casesTotal: 7

Autism spectrum disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001386298.1. 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		1 clinvar	14 clinvar	202 clinvar	2 clinvar	219
missense	1 clinvar	12 clinvar	547 clinvar	138 clinvar	3 clinvar	701
nonsense	6 clinvar	11 clinvar	11 clinvar	1 clinvar		29
start loss						0
frameshift	25 clinvar	34 clinvar	17 clinvar			76
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	13 clinvar			20
Total	34	63	602	341	5	1045

Highest pathogenic variant AF is 0.00000821145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001386298.1	RefSeq	NP_001373227.1	20	MANE Select
ENST00000681038.1	Ensembl	ENSP00000505728.1	20	MANE Select
NM_001304815.2	RefSeq	NP_001291744.1	20	Standard
NM_001379480.1	RefSeq	NP_001366409.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cicb	Danio rerio	Structure: primitive erythrocyte differentiation Quality: increased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

cicb

Danio rerio

Structure: primitive erythrocyte differentiation

Quality: increased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
brain development
learning
memory
social behavior

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
chromatin binding
protein binding

Cellular Component

nucleus
nucleoplasm
protein-containing complex
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000575354
Coding exons: 20
Length: 27261
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.726	904	968	0.934	0.0000644	9995
Missense (PolyPhen)		305	422.99	0.72107		4198
Synonymous	-4.48	545	427	1.28	0.0000297	3758
Loss of Function	6.02	4	49.9	0.0801	0.00000259	602

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional repressor which plays a role in development of the central nervous system (CNS). In concert with ATXN1 and ATXN1L, involved in brain development. {ECO:0000250|UniProtKB:Q924A2}.;

Recessive Scores

pRec: 0.176

Intolerance Scores

LoFtool: 0.0161
RVIS EVS: -3.38
RVIS percentile EVS: 0.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.757

Gene Damage Prediction

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