rs28634999

Variant names:

• chr14-104793964-C-T
• rs28634999
• ENST00000402615.6:c.-917G>A

Variant summary

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

The ENST00000402615.6(AKT1):​c.-917G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 152,290 control chromosomes in the GnomAD database, including 223 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 0.036 (223 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKT1 ENST00000402615.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.16
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0897 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000402615.6. 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
	AKT1	NM_001382430.1	MANE Select	c.-257-660G>A		intron	N/A	NP_001369359.1
	AKT1	NM_001014431.2		c.-79-1242G>A		intron	N/A	NP_001014431.1
	AKT1	NM_001014432.2		c.-163-754G>A		intron	N/A	NP_001014432.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000402615.6	TSL:1	c.-917G>A		5_prime_UTR	Exon 1 of 14	ENSP00000385326.2
	AKT1	ENST00000554581.5	TSL:1	c.-1321G>A		5_prime_UTR	Exon 1 of 13	ENSP00000451828.1
	AKT1	ENST00000649815.2	MANE Select	c.-257-660G>A		intron	N/A	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5519 AN: 152172 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0315

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 112 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 74

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0363 AC: 5525 AN: 152290 Hom.: 223 Cov.: 33 AF XY: 0.0354 AC XY: 2640 AN XY: 74480

African (AFR) AF: 0.0922 AC: 3828 AN: 41538

American (AMR) AF: 0.0271 AC: 415 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5178

South Asian (SAS) AF: 0.0393 AC: 190 AN: 4830

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 927 AN: 68016

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0171 Hom.: 64

Bravo AF: 0.0399

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.45
PhyloP100		-2.2
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs28634999; hg19: chr14-105260301;