CCDC88A

protein-coding

coiled-coil domain containing 88A

Gene summary

This gene encodes a member of the Girdin family of coiled-coil domain containing proteins. The encoded protein is an actin-binding protein that is activated by the serine/threonine kinase Akt and plays a role in cytoskeleton remodeling and cell migration. The encoded protein also enhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependent activation of Akt by growth factor receptor tyrosine kinases and G protein-coupled receptors. Increased expression of this gene and phosphorylation of the encoded protein may play a role in cancer metastasis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

Previous symbols:

KIAA1212

MANE transcript

NM_001365480.1

Inheritance

ClinVar variants

P:38U:513B:369

Top phenotype

PEHO-like syndrome

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr2:55,287,842-55,419,895

External References & Databases

Ensembl (ENSG00000115355)

Transcript & Mutation Effects

hg38 • Region Span ~132.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PEHO-like syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020495

Submitter: Labcorp Genetics (formerly Invitae)

PEHO-like syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0020495

Submitter: G2P

PEHO-like syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020495

Submitter: Orphanet

Clinical Genomic Database (CGD)

PEHO-like syndromeAR

Manifestation: Craniofacial; 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: 26917597

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CCDC88A variants in ClinVar

8 Conditions Cataloged

not providedTotal: 1022

not specifiedTotal: 230

PEHO-like syndromeTotal: 16

CCDC88A-related disorderTotal: 13

Autism spectrum disorderTotal: 1

Developmental delayTotal: 1

MicrocephalyTotal: 1

PEHO syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001365480.1. 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			12 clinvar	337 clinvar	7 clinvar	356
missense		1 clinvar	496 clinvar	16 clinvar	7 clinvar	520
nonsense	13 clinvar		2 clinvar			15
start loss						0
frameshift	19 clinvar	1 clinvar				20
splice donor/acceptor (+/-2bp)		4 clinvar	3 clinvar	2 clinvar		9
Total	32	6	513	355	14	920

Highest pathogenic variant AF is 0.0000065765244

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001365480.1	RefSeq	NP_001352409.1	32	MANE Select
ENST00000436346.7	Ensembl	ENSP00000410608.1	32	MANE Select
NM_001135597.2	RefSeq	NP_001129069.1	32	Standard
NM_001254943.2	RefSeq	NP_001241872.1	33	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mesodermal Commitment Pathway

Biological Process

regulation of protein phosphorylation
DNA replication
regulation of DNA replication
regulation of neuron projection development
cell migration

Molecular Function

actin binding
microtubule binding
phosphatidylinositol binding
protein homodimerization activity
protein kinase B binding

Cellular Component

cytoplasm
endoplasmic reticulum
Golgi apparatus
centrosome
centriole

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000336838
Coding exons: 32
Length: 132080
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.35	678	873	0.776	0.0000432	12365
Missense (PolyPhen)		220	335.94	0.65489		4999
Synonymous	-0.175	317	313	1.01	0.0000152	3279
Loss of Function	8.66	7	101	0.0695	0.00000558	1329

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000068	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000047	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Enhances phosphoinositide 3-kinase (PI3K)- dependent phosphorylation and kinase activity of AKT1/PKB, but does not possess kinase activity itself (By similarity). Phosphorylation of AKT1/PKB thereby induces the phosphorylation of downstream effectors GSK3 and FOXO1/FKHR, and regulates DNA replication and cell proliferation (By similarity). Essential for the integrity of the actin cytoskeleton and for cell migration (PubMed:16139227). Required for formation of actin stress fibers and lamellipodia (PubMed:15882442). May be involved in membrane sorting in the early endosome (PubMed:15882442). Plays a role in ciliogenesis and cilium morphology and positioning and this may partly be through regulation of the localization of scaffolding protein CROCC/Rootletin (PubMed:27623382). {ECO:0000250|UniProtKB:Q5SNZ0, ECO:0000269|PubMed:15882442, ECO:0000269|PubMed:16139227, ECO:0000269|PubMed:27623382}.;
Disease: DISEASE: PEHO-like syndrome (PEHOL) [MIM:617507]: An autosomal recessive syndrome characterized by microcephaly and moderately severe hypotonia manifesting at birth, seizures that progress into infantile spasms with hypsarrhythmia, brain atrophy with bilateral polymicrogyria and pachygyria, thin corpus callosum, and mild reduction in cerebellar vermis volume. Patients also display optic atrophy, severe cognitive delay, puffiness of the maxillary region of the face, and edema of the dorsum of the hands and feet. {ECO:0000269|PubMed:26917597}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.487
RVIS EVS: -1.57
RVIS percentile EVS: 3.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.840

Gene Damage Prediction

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