ASXL2

protein-coding

ASXL transcriptional regulator 2

Gene summary

This gene encodes a member of a family of epigenetic regulators that bind various histone-modifying enzymes and are involved in the assembly of transcription factors at specific genomic loci. Naturally occurring mutations in this gene are associated with cancer in several tissue types (breast, bladder, pancreas, ovary, prostate, and blood). This gene plays an important role in neurodevelopment, cardiac function, adipogenesis, and osteoclastogenesis. [provided by RefSeq, Feb 2017]

MANE transcript

NM_018263.6

Inheritance

ClinVar variants

P:30U:351B:256

Top phenotype

Shashi-Pena syndrome

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr2:25,733,753-25,878,487

External References & Databases

Ensembl (ENSG00000143970)

Transcript & Mutation Effects

hg38 • Region Span ~144.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Truncating ASXL2 variants were first reported in relation to syndromic intellectual disability in 2016 (Shashi et al., 2016; PMID 27693232). ASXL2 encodes a chromatin protein involved in transcriptional regulation. Clinical features in affected individuals include variable developmental or intellectual impairments, macrocephaly, distinct facial dysmorphisms, facial nevus flammeus, neonatal feeding difficulties, and hypotonia. The mechanism of pathogenicity is proposed to be dominant negative since variants cluster in the last and penultimate exons and cDNA studies on three probands showed that the mutant transcripts escape nonsense-mediated mRNA decay (PMID: 27693232). At least 10 unique nonsense and frameshift variants have been reported in 10 probands included in this curation (PMIDs: 27693232, 33751773, 29907797, 33057194, 27479843, 28135719). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants are de novo in all probands. This gene-disease association is also supported by experimental evidence. The ASXL gene family (ASXL1, ASXL2, and ASXL3) participates in body patterning during embryogenesis and encodes proteins involved in epigenetic and transcriptional regulation (PMID: 23736028). Germline de novo truncating variants in ASXL1 and ASXL3 have been implicated in Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of intellectual disability and dysmorphic features (PMIDs: 21706002, 23383720). In summary, ASXL2 is definitively associated with autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 09/28/2021 (SOP Version 8).

Shashi-Pena syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014963

Submitter: G2P

Shashi-Pena syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014963

Submitter: Illumina

Shashi-Pena syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014963

Submitter: Labcorp Genetics (formerly Invitae)

Shashi-Pena syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014963

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Shashi-Pena syndromeAD

Manifestation: Cardiovascular; Craniofacial; Endocrine; Dermatologic; Neurologic

Intervention: Cardiovascular

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Refs: 27693232

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASXL2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 457

Inborn genetic diseasesTotal: 205

not specifiedTotal: 77

Shashi-Pena syndromeTotal: 70

ASXL2-related disorderTotal: 57

Syndromic intellectual disabilityTotal: 4

Neurodevelopmental disorderTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018263.6. 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	139 clinvar	7 clinvar	151
missense		2 clinvar	334 clinvar	91 clinvar	18 clinvar	445
nonsense	4 clinvar	4 clinvar	3 clinvar			11
start loss						0
frameshift	9 clinvar	10 clinvar	6 clinvar			25
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar	1 clinvar		5
Total	13	17	351	231	25	637

Highest pathogenic variant AF is 0.000008059336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018263.6	RefSeq	NP_060733.4	13	MANE Select
ENST00000435504.9	Ensembl	ENSP00000391447.3	13	MANE Select
NM_001369346.1	RefSeq	NP_001356275.1	10	Standard
NM_001369347.1	RefSeq	NP_001356276.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
UCH proteinases
Deubiquitination

Biological Process

transcription, DNA-templated
animal organ morphogenesis
protein deubiquitination
positive regulation of peroxisome proliferator activated receptor signaling pathway
positive regulation of fat cell differentiation

Molecular Function

DNA binding
chromatin binding
peroxisome proliferator activated receptor binding
metal ion binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
PR-DUB complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000435504
Coding exons: 13
Length: 144764
Individuals with no LoFs: 124630
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 124641
p: 0.0000441

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.71	609	740	0.823	0.0000375	9309
Missense (PolyPhen)		154	255.77	0.6021		3263
Synonymous	-1.40	315	285	1.11	0.0000157	2947
Loss of Function	6.37	3	53.2	0.0564	0.00000268	693

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.00013	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility (By similarity). Involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as peroxisome proliferator-activated receptor gamma (PPARG). Acts as coactivator for PPARG and enhances its adipocyte differentiation-inducing activity; the function seems to involve differential recruitment of acetylated and methylated histone H3. {ECO:0000250, ECO:0000269|PubMed:21047783}.;
Disease: DISEASE: Shashi-Pena syndrome (SHAPNS) [MIM:617190]: An autosomal dominant syndrome characterized by delayed psychomotor development, intellectual disability of variable severity, macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, and hypotonia. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures. {ECO:0000269|PubMed:27693232}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving ASXL2 is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with KAT6A generates a KAT6A-ASXL2 fusion protein.;

Recessive Scores

pRec: 0.0771

Essentials

Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.626

Gene Damage Prediction

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