APC2

protein-coding

APC regulator of WNT signaling pathway 2, the group of Armadillo repeat containing

Gene summary

This gene encodes a strongly conserved protein that has an N-terminal coiled-coil domain followed by an armadillo domain, five 20-amino acid repeats, and two SAMP domains. This protein promotes the assembly of a multiprotein complex that recruits and phosphorylates the Wnt effector beta-catenin and targets beta-catenin for ubiquitylation and proteasomal degradation. This protein therefore plays a role in the reduction of cytoplasmic levels of beta-catenin which in turn reduces activation of Wnt target genes that play a pivotal role in the pathogenesis of various human cancers. The protein encoded by this gene is closely related to the adenomatous polyposis coli (APC) tumor-suppressor protein and has similar tumor-suppressor effects. This gene also plays a role in actin assembly, cell-cell adhesion, and microtubule network formation through its interaction with cytoskeletal proteins. This gene has its highest expression in the central nervous system and is involved in brain development through cytoskeletal regulation in neurons. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

MANE transcript

NM_005883.3

Inheritance

AR, AD

ClinVar variants

P:29U:704B:425

Top phenotype

Intellectual developmental disorder, autosomal recessive 74 (Sotos syndrome 3); Cortical dysplasia, complex, with other brain malformations 10

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr19:1,446,302-1,473,244

External References & Databases

Ensembl (ENSG00000115266)

Transcript & Mutation Effects

hg38 • Region Span ~26.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lissencephaly spectrum disordersSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018838

Submitter: ClinGen

APC2 was first reported in relation to autosomal recessive lissencephaly spectrum disorders by Lee et al. in 2019 (PMID 31585108). Individuals with lissencephaly spectrum disorders related to APC2 pathogenic variants present with posterior predominant lissencephaly +/- corpus callosum dysgenesis, hypoplasia of the cerebellum, severe developmental delay , epilepsy with myoclonic or generalized tonic-clonic seizures. At least 9 unique variants predicted to cause loss of function have been reported in humans in association with autosomal recessive lissencephaly spectrum disorders . Evidence supporting this gene-disease relationship includes experimental data implicating APC2 plays a role in microtubule function at the axonal growth cone and Apc2 -/- mouse models demonstrating defects in the cortical lamina, as well as the cerebellum. Of note, this gene has also been implicated in Sotos Syndrome Type 3 which features intellectual disability and characteristic facial features. This association will be assessed separately in the future. Three years have elapsed since the first association between APC2 and lissencephaly spectrum disorders, so a definitive classification is warranted. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on October 11, 2022 (SOP Version 9).

cortical dysplasia, complex, with other brain malformations 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032866

Submitter: Labcorp Genetics (formerly Invitae)

cortical dysplasia, complex, with other brain malformations 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032866

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 74LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014951

Submitter: Labcorp Genetics (formerly Invitae)

cortical dysplasia, complex, with other brain malformations 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032866

Submitter: G2P

Sotos syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019349

Submitter: Orphanet

cortical dysplasia, complex, with other brain malformations 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032866

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 74 (Sotos syndrome 3); Cortical dysplasia, complex, with other brain malformations 10AR

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: 25753423; 31585108

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to APC2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 813

Inborn genetic diseasesTotal: 492

APC2-related disorderTotal: 81

not specifiedTotal: 70

Intellectual developmental disorder, autosomal recessive 74Total: 35

Cortical dysplasia, complex, with other brain malformations 10Total: 31

Complex cortical dysplasia with other brain malformations 1Total: 1

Esophageal atresia/tracheoesophageal fistulaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005883.3. 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			2 clinvar	355 clinvar	18 clinvar	375
missense	1 clinvar	1 clinvar	696 clinvar	41 clinvar	11 clinvar	750
nonsense	3 clinvar	1 clinvar	2 clinvar			6
start loss						0
frameshift	9 clinvar	11 clinvar	3 clinvar			23
splice donor/acceptor (+/-2bp)		3 clinvar	1 clinvar			4
Total	13	16	704	396	29	1158

Highest pathogenic variant AF is 0.0000058943933

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005883.3	RefSeq	NP_005874.1	14	MANE Select
ENST00000590469.6	Ensembl	ENSP00000467073.2	14	MANE Select
NM_001351273.1	RefSeq	NP_001338202.1	14	Standard
ENST00000233607.6	Ensembl	ENSP00000233607.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric cancer - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Breast cancer - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

microtubule cytoskeleton organization
cell fate specification
negative regulation of microtubule depolymerization
pattern specification process
Wnt signaling pathway

Molecular Function

protein binding
beta-catenin binding
microtubule binding
gamma-catenin binding

Cellular Component

cytoplasm
Golgi apparatus
cytosol
cytoplasmic microtubule
actin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000535453
Coding exons: 14
Length: 26944
Individuals with no LoFs: 125471
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125486
p: 0.0000598

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.754	1015	1.08e+3	0.936	0.0000664	14009
Missense (PolyPhen)		280	405.78	0.69003		5077
Synonymous	-2.43	583	513	1.14	0.0000345	5159
Loss of Function	6.24	7	58.5	0.120	0.00000290	702

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000078	0.000062	rare
Latino/Admixed American	0.000064	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00012	0.00011	rare
Finnish	0.00010	0.000092	rare
European (Non-Finnish)	0.000058	0.000053	rare
South Asian	0.000068	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Stabilizes microtubules and may regulate actin fiber dynamics through the activation of Rho family GTPases (PubMed:25753423). May also function in Wnt signaling by promoting the rapid degradation of CTNNB1 (PubMed:10021369, PubMed:11691822, PubMed:9823329). {ECO:0000269|PubMed:10021369, ECO:0000269|PubMed:11691822, ECO:0000269|PubMed:25753423, ECO:0000269|PubMed:9823329}.;
Disease: DISEASE: Sotos syndrome 3 (SOTOS3) [MIM:617169]: A form of Sotos syndrome, a childhood overgrowth syndrome characterized by prenatal and postnatal overgrowth, developmental delay, mental retardation, advanced bone age, and abnormal craniofacial morphology. SOTOS3 patients do not have advanced bone age, hypotonia, seizures, or autism. SOTOS3 transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:25753423}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.142

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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