rs10138227

Variant names:

• chr14-104793369-C-T
• rs10138227
• ENST00000402615.6:c.-322G>A

Variant summary

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

The NM_005163.2(AKT1):​c.-322G>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 0.151 in 205,896 control chromosomes in the GnomAD database, including 2,583 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 0.16 (2113 hom., cov: 33)
  • Exomes 𝑓: 0.13 (470 hom.)
• Consequence: AKT1 NM_005163.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.66
• Publications: 23 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005163.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	NM_001382430.1	MANE Select	c.-257-65G>A		intron	N/A	NP_001369359.1
	AKT1	NM_005163.2		c.-322G>A		5_prime_UTR	Exon 1 of 14	NP_005154.2
	AKT1	NM_001014431.2		c.-79-647G>A		intron	N/A	NP_001014431.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000402615.6	TSL:1	c.-322G>A		5_prime_UTR	Exon 1 of 14	ENSP00000385326.2
	AKT1	ENST00000554581.5	TSL:1	c.-726G>A		5_prime_UTR	Exon 1 of 13	ENSP00000451828.1
	AKT1	ENST00000555528.5	TSL:1	c.-322G>A		5_prime_UTR	Exon 1 of 14	ENSP00000450688.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23970 AN: 152112 Hom.: 2111 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.131 AC: 7024 AN: 53666 Hom.: 470 Cov.: 0 AF XY: 0.128 AC XY: 3192 AN XY: 24936

African (AFR) AF: 0.227 AC: 499 AN: 2202

American (AMR) AF: 0.133 AC: 200 AN: 1504

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 380 AN: 3314

East Asian (EAS) AF: 0.142 AC: 1230 AN: 8648

South Asian (SAS) AF: 0.0881 AC: 43 AN: 488

European-Finnish (FIN) AF: 0.0789 AC: 6 AN: 76

Middle Eastern (MID) AF: 0.0697 AC: 23 AN: 330

European-Non Finnish (NFE) AF: 0.124 AC: 4031 AN: 32636

Other (OTH) AF: 0.137 AC: 612 AN: 4468

GnomAD4 genome AF: 0.158 AC: 23999 AN: 152230 Hom.: 2113 Cov.: 33 AF XY: 0.154 AC XY: 11482 AN XY: 74428

African (AFR) AF: 0.226 AC: 9381 AN: 41528

American (AMR) AF: 0.132 AC: 2013 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3470

East Asian (EAS) AF: 0.103 AC: 532 AN: 5176

South Asian (SAS) AF: 0.0870 AC: 420 AN: 4826

European-Finnish (FIN) AF: 0.116 AC: 1233 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9572 AN: 67998

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.150 Hom.: 836

Bravo AF: 0.163

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.073
DANN	Benign	0.59
PhyloP100		-3.7
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.2
Mutation Taster		=300/0	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: rs10138227; hg19: chr14-105259706; COSMIC: COSV62571388;