rs1130214

Variant names:

• chr14-104793397-C-A
• rs1130214
• ENST00000402615.6:c.-350G>T

Variant summary

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

The NM_005163.2(AKT1):​c.-350G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 208,470 control chromosomes in the GnomAD database, including 9,203 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 0.30 (7346 hom., cov: 33)
  • Exomes 𝑓: 0.25 (1857 hom.)
• Consequence: AKT1 NM_005163.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.808
• Publications: 135 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	NM_001382430.1	MANE Select	c.-257-93G>T		intron	N/A	NP_001369359.1	B0LPE5
	AKT1	NM_005163.2		c.-350G>T		5_prime_UTR	Exon 1 of 14	NP_005154.2	P31749-1
	AKT1	NM_001014431.2		c.-79-675G>T		intron	N/A	NP_001014431.1	B0LPE5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000402615.6	TSL:1	c.-350G>T		5_prime_UTR	Exon 1 of 14	ENSP00000385326.2	P31749-1
	AKT1	ENST00000554581.5	TSL:1	c.-754G>T		5_prime_UTR	Exon 1 of 13	ENSP00000451828.1	P31749-1
	AKT1	ENST00000555528.5	TSL:1	c.-350G>T		5_prime_UTR	Exon 1 of 14	ENSP00000450688.1	P31749-1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45855 AN: 152034 Hom.: 7340 Cov.: 33

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.248 AC: 13982 AN: 56318 Hom.: 1857 Cov.: 0 AF XY: 0.247 AC XY: 6457 AN XY: 26104

African (AFR) AF: 0.369 AC: 873 AN: 2368

American (AMR) AF: 0.228 AC: 354 AN: 1552

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 815 AN: 3506

East Asian (EAS) AF: 0.143 AC: 1290 AN: 9016

South Asian (SAS) AF: 0.197 AC: 94 AN: 476

European-Finnish (FIN) AF: 0.219 AC: 21 AN: 96

Middle Eastern (MID) AF: 0.174 AC: 59 AN: 340

European-Non Finnish (NFE) AF: 0.269 AC: 9224 AN: 34276

Other (OTH) AF: 0.267 AC: 1252 AN: 4688

GnomAD4 genome AF: 0.302 AC: 45895 AN: 152152 Hom.: 7346 Cov.: 33 AF XY: 0.297 AC XY: 22061 AN XY: 74374

African (AFR) AF: 0.376 AC: 15588 AN: 41504

American (AMR) AF: 0.247 AC: 3775 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 875 AN: 3470

East Asian (EAS) AF: 0.105 AC: 543 AN: 5168

South Asian (SAS) AF: 0.182 AC: 878 AN: 4832

European-Finnish (FIN) AF: 0.294 AC: 3116 AN: 10600

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20169 AN: 67974

Other (OTH) AF: 0.287 AC: 605 AN: 2110

Alfa AF: 0.291 Hom.: 2763

Bravo AF: 0.303

Asia WGS AF: 0.137 AC: 475 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.47
DANN	Benign	0.71
PhyloP100		-0.81
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs1130214; hg19: chr14-105259734; COSMIC: COSV62575196;