14-104774548-C-G

Variant names:

• chr14-104774548-C-G
• rs2494734
• NM_001382430.1:c.633+390G>C

Variant summary

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

The NM_001382430.1(AKT1):​c.633+390G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 255,446 control chromosomes in the GnomAD database, including 44,426 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 0.61 (31055 hom., cov: 34)
  • Exomes 𝑓: 0.49 (13371 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80
• Publications: 13 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.633+390G>C		intron_variant	Intron 8 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.633+390G>C		intron_variant	Intron 8 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92769 AN: 152066 Hom.: 31009 Cov.: 34

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.587

GnomAD4 exome AF: 0.491 AC: 50700 AN: 103262 Hom.: 13371 Cov.: 0 AF XY: 0.494 AC XY: 25976 AN XY: 52630

African (AFR) AF: 0.886 AC: 3017 AN: 3404

American (AMR) AF: 0.640 AC: 3064 AN: 4790

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1460 AN: 3510

East Asian (EAS) AF: 0.601 AC: 4136 AN: 6878

South Asian (SAS) AF: 0.553 AC: 4462 AN: 8064

European-Finnish (FIN) AF: 0.477 AC: 2201 AN: 4618

Middle Eastern (MID) AF: 0.494 AC: 258 AN: 522

European-Non Finnish (NFE) AF: 0.444 AC: 28919 AN: 65094

Other (OTH) AF: 0.499 AC: 3183 AN: 6382

GnomAD4 genome AF: 0.610 AC: 92871 AN: 152184 Hom.: 31055 Cov.: 34 AF XY: 0.613 AC XY: 45570 AN XY: 74400

African (AFR) AF: 0.890 AC: 36976 AN: 41552

American (AMR) AF: 0.638 AC: 9756 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3472

East Asian (EAS) AF: 0.649 AC: 3348 AN: 5162

South Asian (SAS) AF: 0.624 AC: 3013 AN: 4828

European-Finnish (FIN) AF: 0.491 AC: 5204 AN: 10592

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.463 AC: 31454 AN: 67968

Other (OTH) AF: 0.587 AC: 1239 AN: 2112

Alfa AF: 0.402 Hom.: 1164

Bravo AF: 0.633

Asia WGS AF: 0.662 AC: 2301 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.34
DANN	Benign	0.38
PhyloP100		-1.8
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)		0.080		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: rs2494734; hg19: chr14-105240885; COSMIC: COSV62575113; COSMIC: COSV62575113;