CC2D1A

protein-coding

coiled-coil and C2 domain containing 1A, the group of C2 domain containing

Gene summary

This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5'-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3). [provided by RefSeq, Jul 2017]

MANE transcript

NM_017721.5

Inheritance

ClinVar variants

P:71U:238B:249

Top phenotype

Intellectual developmental disorder, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr19:13,906,201-13,930,879

External References & Databases

Ensembl (ENSG00000132024)

Transcript & Mutation Effects

hg38 • Region Span ~24.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012037

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*CC2D1A* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2005 (Basel-Vanagaite et al., PMID: 16033914). At least 5 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and segregation data. This gene-disease relationship is also supported by experimental evidence, including mouse models and expression studies. In summary, there is definitive evidence supporting the relationship between *CC2D1A* and autosomal recessive 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 8, 2020 (SOP version 6).

intellectual developmental disorder, autosomal recessive 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012037

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012037

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 3AR

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: 16033914; 17149387

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CC2D1A variants in ClinVar

14 Conditions Cataloged

not providedTotal: 509

Inborn genetic diseasesTotal: 289

not specifiedTotal: 116

Intellectual disability, autosomal recessive 3Total: 75

CC2D1A-related disorderTotal: 41

Intellectual disabilityTotal: 5

CiliopathyTotal: 2

Smith-Magenis Syndrome-likeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017721.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	176 clinvar	3 clinvar	184
missense		1 clinvar	225 clinvar	66 clinvar	2 clinvar	294
nonsense	7 clinvar	6 clinvar				13
start loss						0
frameshift	15 clinvar	12 clinvar	3 clinvar			30
splice donor/acceptor (+/-2bp)	5 clinvar	25 clinvar	5 clinvar	2 clinvar		37
Total	27	44	238	244	5	558

Highest pathogenic variant AF is 0.00006478371

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017721.5	RefSeq	NP_060191.3	29	MANE Select
ENST00000318003.11	Ensembl	ENSP00000313601.6	29	MANE Select
NM_001411138.1	RefSeq	NP_001398067.1	29	Standard
ENST00000586955.5	Ensembl	ENSP00000465376.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
EGFR1

Biological Process

negative regulation of transcription by RNA polymerase II
positive regulation of I-kappaB kinase/NF-kappaB signaling

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription repressor activity, RNA polymerase II-specific
protein binding
cadherin binding

Cellular Component

fibrillar center
nucleus
microtubule organizing center
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000318003
Coding exons: 29
Length: 24679
Individuals with no LoFs: 124739
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 124805
p: 0.000264

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.941	541	606	0.892	0.0000402	6060
Missense (PolyPhen)		172	199.42	0.86249		1987
Synonymous	0.212	247	251	0.983	0.0000170	1983
Loss of Function	4.99	15	55.0	0.273	0.00000286	615

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.0019	0.0017	notable
East Asian	0.00045	0.00045	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00037	0.00036	rare
Other	0.00051	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells. The combination of calcium and ATP specifically inactivates the binding with FRE. May play a role in the altered regulation of HTR1A associated with anxiety and major depression. Mediates HDAC-independent repression of HTR1A promoter in neuronal cell. Performs essential function in controlling functional maturation of synapses (By similarity). Plays distinct roles depending on its localization. When cytoplasmic, acts as a scaffold protein in the PI3K/PDK1/AKT pathway. Repressor of HTR1A when nuclear. In the centrosome, regulates spindle pole localization of the cohesin subunit SCC1/RAD21, thereby mediating centriole cohesion during mitosis. {ECO:0000250, ECO:0000269|PubMed:20171170}.;
Disease: DISEASE: Mental retardation, autosomal recessive 3 (MRT3) [MIM:608443]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs. {ECO:0000269|PubMed:16033914}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.719
RVIS EVS: 1.45
RVIS percentile EVS: 95.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.972

Gene Damage Prediction

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