rs1130214

Positions:

• chr14-104793397-C-A

Variant summary

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

The NM_001382430.1(AKT1):​c.-257-93G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 208,470 control chromosomes in the GnomAD database, including 9,203 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 0.30 (7346 hom., cov: 33)
  • Exomes 𝑓: 0.25 (1857 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.808

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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.-257-93G>T		intron_variant		ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.-257-93G>T		intron_variant			NM_001382430.1	ENSP00000497822	P1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45855 AN: 152034 Hom.: 7340 Cov.: 33

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.248 AC: 13982 AN: 56318 Hom.: 1857 Cov.: 0 AF XY: 0.247 AC XY: 6457 AN XY: 26104

Gnomad4 AFR exome AF: 0.369

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.267

GnomAD4 genome AF: 0.302 AC: 45895 AN: 152152 Hom.: 7346 Cov.: 33 AF XY: 0.297 AC XY: 22061 AN XY: 74374

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.287

Alfa AF: 0.294 Hom.: 1667

Bravo AF: 0.303

Asia WGS AF: 0.137 AC: 475 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.47
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs1130214; hg19: chr14-105259734; COSMIC: COSV62575196; COSMIC: COSV62575196;