rs2498796

Variant names:

• chr14-104776883-G-A
• rs2498796
• NM_001382430.1:c.176-113C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382430.1(AKT1):​c.176-113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 808,566 control chromosomes in the GnomAD database, including 48,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9143 hom., cov: 33)
  • Exomes 𝑓: 0.33 (39152 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.249
• Publications: 17 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 Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-104776883-G-A is Benign according to our data. Variant chr14-104776883-G-A is described in ClinVar as Benign. ClinVar VariationId is 1264628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.176-113C>T		intron_variant	Intron 4 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.176-113C>T		intron_variant	Intron 4 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51457 AN: 151954 Hom.: 9147 Cov.: 33

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.327

GnomAD4 exome AF: 0.334 AC: 219287 AN: 656494 Hom.: 39152 Cov.: 9 AF XY: 0.339 AC XY: 115106 AN XY: 339944

African (AFR) AF: 0.318 AC: 5345 AN: 16802

American (AMR) AF: 0.476 AC: 12266 AN: 25766

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 4560 AN: 16190

East Asian (EAS) AF: 0.566 AC: 17768 AN: 31402

South Asian (SAS) AF: 0.449 AC: 24745 AN: 55068

European-Finnish (FIN) AF: 0.339 AC: 10691 AN: 31572

Middle Eastern (MID) AF: 0.346 AC: 963 AN: 2782

European-Non Finnish (NFE) AF: 0.297 AC: 131960 AN: 444100

Other (OTH) AF: 0.335 AC: 10989 AN: 32812

GnomAD4 genome AF: 0.339 AC: 51482 AN: 152072 Hom.: 9143 Cov.: 33 AF XY: 0.344 AC XY: 25604 AN XY: 74350

African (AFR) AF: 0.320 AC: 13257 AN: 41452

American (AMR) AF: 0.429 AC: 6560 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3155 AN: 5168

South Asian (SAS) AF: 0.490 AC: 2367 AN: 4826

European-Finnish (FIN) AF: 0.334 AC: 3540 AN: 10592

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20552 AN: 67950

Other (OTH) AF: 0.330 AC: 697 AN: 2114

Alfa AF: 0.321 Hom.: 981

Bravo AF: 0.344

Asia WGS AF: 0.530 AC: 1842 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2498796; hg19: chr14-105243220; COSMIC: COSV62573593; COSMIC: COSV62573593;