Variant rs10138227 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000402615.6(AKT1):c.-322G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 205,896 control chromosomes in the GnomAD database, including 2,583 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2113 hom., cov: 33)

Exomes 𝑓: 0.13 ( 470 hom. )

Consequence

AKT1
ENST00000402615.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.66

Variant links:

Genes affected

AKT1 (HGNC:391): (AKT serine/threonine kinase 1) This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

AKT1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT1	NM_001382430.1 linkuse as main transcript	c.-257-65G>A		intron_variant		ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2 linkuse as main transcript	c.-257-65G>A		intron_variant			NM_001382430.1	ENSP00000497822	P1	P31749-1

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

23970

AN:

152112

Hom.:

2111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.0859

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.147

GnomAD4 exome

AF:

0.131

AC:

7024

AN:

53666

Hom.:

470

Cov.:

AF XY:

0.128

AC XY:

3192

AN XY:

24936

show subpopulations

Gnomad4 AFR exome

AF:

0.227

Gnomad4 AMR exome

AF:

0.133

Gnomad4 ASJ exome

AF:

0.115

Gnomad4 EAS exome

AF:

0.142

Gnomad4 SAS exome

AF:

0.0881

Gnomad4 FIN exome

AF:

0.0789

Gnomad4 NFE exome

AF:

0.124

Gnomad4 OTH exome

AF:

0.137

GnomAD4 genome

AF:

0.158

AC:

23999

AN:

152230

Hom.:

2113

Cov.:

AF XY:

0.154

AC XY:

11482

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.226

Gnomad4 AMR

AF:

0.132

Gnomad4 ASJ

AF:

0.122

Gnomad4 EAS

AF:

0.103

Gnomad4 SAS

AF:

0.0870

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.141

Gnomad4 OTH

AF:

0.149

Alfa

AF:

0.149

Hom.:

700

Bravo

AF:

0.163

Asia WGS

AF:

0.0970

AC:

337

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.073

DANN

Benign

0.59

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over