rs10138227

chr14-104793369-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.66

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]

ACMG classification

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	UniProt
AKT1	NM_001382430.1	c.-257-65G>A		intron_variant		ENST00000649815.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23970 AN: 152112 Hom.: 2111 Cov.: 33

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.: 0 AF XY: 0.128 AC XY: 3192 AN XY: 24936

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.: 33 AF XY: 0.154 AC XY: 11482 AN XY: 74428

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

Other links and lift over

dbSNP: rs10138227; hg19: chr14-105259706; COSMIC: COSV62571388; COSMIC: COSV62571388;