rs2494737

Positions:

• chr14-104779988-T-A
• chr14-104779988-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382430.1(AKT1):​c.175+100A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,502,850 control chromosomes in the GnomAD database, including 94,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13279 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81205 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-104779988-T-A is Benign according to our data. Variant chr14-104779988-T-A is described in ClinVar as [Benign]. Clinvar id is 695299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1	c.175+100A>T		intron_variant		ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2	c.175+100A>T		intron_variant			NM_001382430.1	P1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61425 AN: 151962 Hom.: 13265 Cov.: 33

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.334 AC: 451706 AN: 1350770 Hom.: 81205 AF XY: 0.338 AC XY: 224650 AN XY: 665046

Gnomad4 AFR exome AF: 0.514

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.617

Gnomad4 SAS exome AF: 0.495

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.404 AC: 61484 AN: 152080 Hom.: 13279 Cov.: 33 AF XY: 0.411 AC XY: 30532 AN XY: 74332

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.355

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.398

Alfa AF: 0.367 Hom.: 1368

Bravo AF: 0.418

Asia WGS AF: 0.591 AC: 2053 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

This variant is associated with the following publications: (PMID: 27259051) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.30
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2494737; hg19: chr14-105246325; COSMIC: COSV62575435; COSMIC: COSV62575435;