ANKLE2

Chr 12AR

ankyrin repeat and LEM domain containing 2

Also known as: KIAA0692, LEMD7, Lem4, MCPH16

NCBI Gene: 23141 ENSG00000176915 UniProt: Q86XL3 OMIM: 616062

This gene encodes a LEM family inner nuclear membrane protein that promotes dephosphorylation of BAF during mitotic exit to facilitate nuclear envelope reassembly and is involved in brain development. Mutations cause primary microcephaly 16, a neurodevelopmental disorder characterized by reduced brain size present from birth. The condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.851 OMIM phenotype

Clinical Summary— ANKLE2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 172 VUS of 376 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.000

Z-score 2.29

OE 0.59 (0.42–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.34Z-score

OE missense 0.96 (0.89–1.03)

509 obs / 531.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.42–0.85)

0≤0.351.4

Missense OE?0.96 (0.89–1.03)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 22 / 37.1Missense obs/exp: 509 / 531.2Syn Z: -1.18

This gene — mechanism propensity

0.6551th %ile

GOF

0.5366th %ile

LOF

0.3454th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

376 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic6

VUS172

Likely Benign91

Benign71

Conflicting9

Pathogenic

Likely Pathogenic

172

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	1	0	4
Likely Pathogenic	3	3	0	0	6
VUS	3	165	4	0	172
Likely Benign	0	36	25	30	91
Benign	0	5	60	6	71
Conflicting	—				9
Total	9	209	90	36	353

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap ANKLE2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →