• 1
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
AKT3 (HGNC:393) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
AKT serine/threonine kinase 3
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
PKBG, RAC-gamma, PRKBG
%HI
2.71(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.18(Read more about gnomAD LOEUF score)
Cytoband
1q43-q44
Genomic Coordinates
GRCh37/hg19: chr1:243651535-244014381 NCBI Ensembl UCSC
GRCh38/hg38: chr1:243488233-243851079 NCBI Ensembl UCSC
MANE Select Transcript
NM_005465.7 ENST00000673466.1 (Read more about MANE Select)
Function
AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an impo... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-3508
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency (1)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
05/09/2023

Haploinsufficiency (HI) Score Details

HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 21800092
    Ballif 2012 (PMID 21800092) described two probands with microcephaly but no seizures or corpus callosum anomalies and small deletions only impacting AKT3. Index patient #10 inherited the deletion from a mother who also presented with microcephaly. Inheritance was unknown for the other proband. The authors propose that the focal deletion likely leading to haploinsufficiency of AKT3 only attributed to the microcephaly phenotype.
  • PUBMED: 25424989
    Gai 2015 (PMID 25424989) described a male proband with microcephaly (OFC on 2nd %tile), hypotonia, gross motor delay, reduced limb strength, poor trunk control, ligamentous laxity and global developmental delay. He was found to have a paternally inherited 396 kilobase deletion that only contained AKT3. Detailed assessment of the father found that he had strabismus, a history of some developmental problems in early years, including hypotonia, poor balance, incoordination, poor spacial awareness, dyspraxia. On examination he was reported to have a sloping forehead, low cranial vault, minor facial asymmetry, a cupids bow upper lip, high/narrow palate, and dental malocclusion with open anterior bite. His intelligence was within normal range. His adult head circumference was normal (50th-98th %tile). The authors suggested that heterozygous loss of AKT3 may not be sufficient to cause microcephaly and cognitive impairment, or may be associated with incomplete penetrance and variable expressivity.
  • PUBMED: 30091983
    Gieldon 2018 (PMID 30091983) reported a female with intellectual disabilities with a reported likely pathogenic de novo deletion, c.437_440delATGA, p.(Asn146Ilefs*5). Clinical information provided on the patient was limited and microcephaly was not described.
HI Evidence Comments:
There have been relatively few reports of putative loss of function variants in AKT3; as described above, these variants have been observed in individuals with variable presentations, including microcephaly and/or developmental delays. Variable expressivity has been described within families. At this time, there is is little evidence to support haploinsufficiency of this gene. Of note, gain of function missense variants in AKT3 have been identified in individuals with overgrowth and/or cerebral malformations (see Gene-Disease Validity curation by the ClinGen Brain Malformations GCEP (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_52b1df18-387f-4c38-a655-682e4d2eb378-2021-07-29T213439.431Z?page=1&size=25&search=). Additional information includes: Ciaccio 2020 32827175 reported a small deletion, c.368_375delCACAAATT which resulted in a frameshift and premature termination of protein, the deletion was absent in gnomAD and HGMD, and classified as pathogenic, the inheritance was unknown. At 6 years old, the proband had microcephaly (-5.15 SD), was underweight (-2.29 SD), and had normal height. Slight facial dysmorphisms were noted (sloping forehead, upslanting palpebral fissures), mild global hypotonia, motor clumsiness, developmental delay. Growth deceleration noted was at 7 months. Brain MRI was non-specific, and included thinning in posterior part of corpus callosum.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
Some recent reports have suggested a role for duplication of AKT3 in macrocephaly. In PMID 23794269, the authors reported a patient with macrocephaly who had a 3 Mb duplication on 1q43q44 that includes AKT3. The authors also found overlapping partial trisomy cases in the medical literature suggesting an association between AKT3 gain and macrocephaly. These reports correspond with the finding that functionally activating mutations in AKT3 cause Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (OMIM 615937). In PMID 24700746, the authors described a boy with significant speech delay and relative macrocephaly [head circumference (HC): 54.9 cm (75th centile)]. They detected a microduplication of 1.06Mb present in four copies at 1q43q44 containing AKT3 and five other RefSeq genes (CEP170, LOC339529, MIR4677, SDCCAG8, and ZNF238). They suggested that this additional case was supportive of AKT3 copy gain as a cause of macrocephaly and impaired speech development. However, as isolated whole AKT3 gene duplication or triplication has not yet been described in the medical literature, the role of AKT3 copy gain in causing macrocephaly remains unclear.

Genomic View

Select assembly: (NC_000001.10) (NC_000001.11)