CIC

Chr 19AD

capicua transcriptional repressor

Also known as: MRD45

NCBI Gene: 23152 ENSG00000079432 UniProt: Q96RK0 OMIM: 612082

This protein functions as a transcriptional repressor that regulates central nervous system development, working in concert with ATXN1 and ATXN1L in brain development. Mutations cause autosomal dominant intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.18), indicating that heterozygous loss is not well-tolerated in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 45MIM #617600

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

799

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 6.02

OE 0.08 (0.04–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.73Z-score

OE missense 0.93 (0.88–0.99)

904 obs / 967.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.18)

0≤0.351.4

Missense OE?0.93 (0.88–0.99)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 4 / 49.9Missense obs/exp: 904 / 967.5Syn Z: -4.48

Background carrier burden — how many people carry a rare variant somewhere in CIC?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 20

2,777 rare PASS variants

Rare truncating (LoF)

1 in 230

192 rare PASS variants

Rare synonymous (reference)

1 in 25

1,499 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CIC. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 22	1 in 210
South Asian	~43k	1 in 18	1 in 440
Remaining (unassigned)	~30k	1 in 17	1 in 180
European (Finnish)	~27k	1 in 61	1 in 380
Admixed American	~22k	1 in 19	1 in 400
African / African American	~21k	1 in 21	1 in 240
East Asian	~20k	1 in 23	1 in 1,300
Ashkenazi Jewish	~13k	1 in 86	1 in 440
Middle Eastern	~2,884	1 in 19	1 in 210

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 20 coding exons well covered in gnomAD exomes; exon 2 poorly covered. Genomes: all 20.? see exons ↓