ANKLE2

protein-coding

ankyrin repeat and LEM domain containing 2, the group of Ankyrin repeat domain containing|LEM domain containing

Gene summary

This gene encodes a member of the LEM family of inner nuclear membrane proteins. The encoded protein functions as a mitotic regulator through postmitotic formation of the nuclear envelope. Mutations in this gene cause morphology defects in the nuclear envelope and BAF hyperphosphorylation. [provided by RefSeq, Mar 2014]

Previous symbols:

KIAA0692

MANE transcript

NM_015114.3

Inheritance

ClinVar variants

P:10U:184B:79

Top phenotype

Microcephaly, primary autosomal recessive, 16

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr12:132,725,503-132,761,832

External References & Databases

Ensembl (ENSG00000176915)

Transcript & Mutation Effects

hg38 • Region Span ~36.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 16, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014730

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly 16, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014730

Submitter: Ambry Genetics

microcephaly 16, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014730

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Microcephaly, primary autosomal recessive, 16AR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Neurologic; Ophthalmologic

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: 25259927

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANKLE2 variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 185

not providedTotal: 114

ANKLE2-related disorderTotal: 24

Microcephaly 16, primary, autosomal recessiveTotal: 20

not specifiedTotal: 12

MicrocephalyTotal: 2

See casesTotal: 2

Vanishing white matter diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015114.3. 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			1 clinvar	31 clinvar	4 clinvar	36
missense		3 clinvar	171 clinvar	44 clinvar		218
nonsense	2 clinvar	2 clinvar	4 clinvar			8
start loss						0
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	6 clinvar			8
Total	3	7	184	75	4	273

Highest pathogenic variant AF is 0.00002328241

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015114.3	RefSeq	NP_055929.1	13	MANE Select
ENST00000357997.10	Ensembl	ENSP00000350686.5	13	MANE Select
ENST00000535036.5	Ensembl	ENSP00000437585.2	3	Standard
ENST00000538766.1	Ensembl	ENSP00000445760.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Initiation of Nuclear Envelope Reformation
Nuclear Envelope Reassembly
Mitotic Anaphase
Mitotic Metaphase and Anaphase
M Phase

Biological Process

mitotic nuclear envelope reassembly
central nervous system development
positive regulation of protein dephosphorylation
negative regulation of phosphorylation
negative regulation of apoptotic process

Molecular Function

protein binding
protein phosphatase regulator activity
protein phosphatase 2A binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357997
Coding exons: 13
Length: 36221
Individuals with no LoFs: 124777
Homozygous LoFs: 0
Heterozygous LoFs: 85
Defined: 124862
p: 0.000340

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.343	509	531	0.958	0.0000318	6073
Missense (PolyPhen)		139	154.97	0.89697		1874
Synonymous	-1.18	247	224	1.10	0.0000157	1898
Loss of Function	2.29	22	37.1	0.593	0.00000204	469

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00019	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00040	0.00039	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00035	0.00034	rare
South Asian	0.00091	0.00072	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit. Coordinates the control of BAF/BANF1 dephosphorylation by inhibiting VRK1 kinase and promoting dephosphorylation of BAF/BANF1 by protein phosphatase 2A (PP2A), thereby facilitating nuclear envelope assembly. It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex. Involved in brain development (PubMed:25259927). {ECO:0000269|PubMed:22770216, ECO:0000269|PubMed:25259927}.;
Disease: DISEASE: Microcephaly 16, primary, autosomal recessive (MCPH16) [MIM:616681]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. {ECO:0000269|PubMed:25259927}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.805
RVIS EVS: -0.08
RVIS percentile EVS: 47.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.644

Gene Damage Prediction

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