ANKLE2

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

Basic information

Region (hg38): 12:132725503-132761832

Previous symbols: [ "KIAA0692" ]

Links

ENSG00000176915 ∙ NCBI:23141 ∙ OMIM:616062 ∙ HGNC:29101 ∙ Uniprot:Q86XL3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microcephaly 16, primary, autosomal recessive (Moderate), mode of inheritance: AR
• microcephaly 16, primary, autosomal recessive (Strong), mode of inheritance: AR
• autosomal recessive primary microcephaly (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly, primary autosomal recessive, 16	AR	General	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	Cardiovascular; Craniofacial; Dermatologic; Neurologic; Ophthalmologic	25259927

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ANKLE2 gene.

• Microcephaly 16, primary, autosomal recessive (1 variants)
• Intellectual disability;Hypotonia;Vanishing white matter disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ANKLE2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				23	6	29
missense		2	97	23	5	127
nonsense	1	1	1			3
start loss						0
frameshift			1			1
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region			4	3		7
non coding				21	59	80
Total	1	4	100	67	70

Variants in ANKLE2

This is a list of pathogenic ClinVar variants found in the ANKLE2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-132727017-C-T			Benign (Aug 17, 2018)
12-132727031-A-T			Benign (Jul 26, 2018)
12-132727125-C-T			Likely benign (Oct 31, 2019)
12-132727234-C-T		ANKLE2-related disorder	Likely benign (Jul 19, 2021)
12-132727250-C-T		ANKLE2-related disorder	Likely benign (Jul 05, 2018)
12-132727251-G-A		ANKLE2-related disorder	Likely benign (Jun 01, 2024)
12-132727252-G-A		Inborn genetic diseases	Uncertain significance (Oct 25, 2024)
12-132727255-A-C		Inborn genetic diseases	Likely benign (Oct 13, 2023)
12-132727279-C-T		Inborn genetic diseases	Uncertain significance (Aug 13, 2021)
12-132727298-C-T		Inborn genetic diseases	Uncertain significance (Jan 05, 2022)
12-132727329-T-C		ANKLE2-related disorder	Likely benign (Apr 29, 2019)
12-132727366-C-T		Inborn genetic diseases	Uncertain significance (May 24, 2024)
12-132727378-C-T		Inborn genetic diseases	Uncertain significance (Feb 09, 2022)
12-132727382-G-A		Inborn genetic diseases	Uncertain significance (Jul 01, 2024)
12-132727387-C-G		Microcephaly 16, primary, autosomal recessive	Benign (May 18, 2021)
12-132727400-G-A		Inborn genetic diseases	Uncertain significance (Oct 02, 2023)
12-132727416-C-A		Inborn genetic diseases	Uncertain significance (Feb 14, 2023)
12-132727447-C-T		Inborn genetic diseases	Uncertain significance (Apr 07, 2021)
12-132727540-G-A			Benign (Jul 17, 2018)
12-132727559-AC-A			Benign (Apr 27, 2019)
12-132727560-C-T			Benign (Jul 17, 2018)
12-132727581-G-A			Benign (Aug 14, 2018)
12-132727587-C-T			Benign (Jul 17, 2018)
12-132727588-A-G			Benign (Jul 17, 2018)
12-132727596-G-A			Benign (Jul 17, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ANKLE2	protein_coding	protein_coding	ENST00000357997	13	36221

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.01e-10	0.978	124777	0	85	124862	0.000340

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.343	509	531	0.958	0.0000318	6073
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000409	0.000406
Ashkenazi Jewish	0.00	0.00
East Asian	0.000399	0.000389
Finnish	0.000234	0.000232
European (Non-Finnish)	0.000347	0.000344
Middle Eastern	0.000399	0.000389
South Asian	0.000915	0.000719
Other	0.000334	0.000329

dbNSFP

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.
• Pathway: Initiation of Nuclear Envelope Reformation;Nuclear Envelope Reassembly;Mitotic Anaphase;Mitotic Metaphase and Anaphase;M Phase;Cell Cycle;Cell Cycle, Mitotic (Consensus)

Intolerance Scores

• loftool: 0.805
• rvis_EVS: -0.08
• rvis_percentile_EVS: 47.22

Haploinsufficiency Scores

• pHI: 0.315
• hipred: Y
• hipred_score: 0.612
• ghis: 0.533

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.644

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ankle2

Gene ontology

• Biological process: mitotic nuclear envelope reassembly;central nervous system development;positive regulation of protein dephosphorylation;negative regulation of phosphorylation;negative regulation of apoptotic process;regulation of phosphoprotein phosphatase activity;regulation of catalytic activity;cell division
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;membrane;integral component of endoplasmic reticulum membrane
• Molecular function: protein binding;protein phosphatase regulator activity;protein phosphatase 2A binding