rs2494732

Positions:

• chr14-104772855-T-C
• chr14-104772855-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.1172+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 1,592,622 control chromosomes in the GnomAD database, including 167,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17643 hom., cov: 33)
  • Exomes 𝑓: 0.45 (149509 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.61

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=-0.92).
• BP6: Variant 14-104772855-T-C is Benign according to our data. Variant chr14-104772855-T-C is described in ClinVar as [Benign]. Clinvar id is 1235718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104772855-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.1172+23A>G		intron_variant		ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.1172+23A>G		intron_variant			NM_001382430.1	ENSP00000497822	P1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72230 AN: 151832 Hom.: 17628 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.468

GnomAD3 exomes AF: 0.499 AC: 114234 AN: 229088 Hom.: 29621 AF XY: 0.492 AC XY: 61217 AN XY: 124444

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.625

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.730

Gnomad SAS exome AF: 0.547

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.450 AC: 648878 AN: 1440672 Hom.: 149509 Cov.: 38 AF XY: 0.452 AC XY: 323372 AN XY: 715580

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.614

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.436

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.466

GnomAD4 genome AF: 0.476 AC: 72298 AN: 151950 Hom.: 17643 Cov.: 33 AF XY: 0.480 AC XY: 35651 AN XY: 74266

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.473

Alfa AF: 0.442 Hom.: 6563

Bravo AF: 0.484

Asia WGS AF: 0.656 AC: 2279 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.40
DANN	Benign	0.55

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: rs2494732; hg19: chr14-105239192; COSMIC: COSV62573275; COSMIC: COSV62573275;