rs2498786

Variant names:

• chr14-104796031-C-G
• rs2498786
• ENST00000855590.1:c.-79-3309G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-104796031-C-G
• chr14-104796031-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000855590.1(AKT1):​c.-79-3309G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,996 control chromosomes in the GnomAD database, including 20,385 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 0.50 (20385 hom., cov: 32)
• Consequence: AKT1 ENST00000855590.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• Proteus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 6

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000855590.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000855590.1		c.-79-3309G>C		intron	N/A	ENSP00000525649.1
	AKT1	ENST00000959648.1		c.-779G>C		upstream_gene	N/A	ENSP00000629707.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75628 AN: 151876 Hom.: 20375 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.527

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75657 AN: 151996 Hom.: 20385 Cov.: 32 AF XY: 0.495 AC XY: 36803 AN XY: 74280

African (AFR) AF: 0.309 AC: 12831 AN: 41496

American (AMR) AF: 0.509 AC: 7774 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2143 AN: 3468

East Asian (EAS) AF: 0.210 AC: 1080 AN: 5146

South Asian (SAS) AF: 0.409 AC: 1971 AN: 4824

European-Finnish (FIN) AF: 0.623 AC: 6572 AN: 10544

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41456 AN: 67928

Other (OTH) AF: 0.522 AC: 1102 AN: 2110

Alfa AF: 0.446 Hom.: 1418

Bravo AF: 0.481

Asia WGS AF: 0.311 AC: 1085 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.4
DANN	Benign	0.56
PhyloP100		1.7
PromoterAI		0.0079	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2498786; hg19: chr14-105262368;