rs2494738

Positions:

• chr14-104780349-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382430.1(AKT1):​c.47-133C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,280,294 control chromosomes in the GnomAD database, including 9,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1503 hom., cov: 33)
  • Exomes 𝑓: 0.089 (7689 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-104780349-G-A is Benign according to our data. Variant chr14-104780349-G-A is described in ClinVar as [Benign]. Clinvar id is 1281679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.47-133C>T		intron_variant		ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.47-133C>T		intron_variant			NM_001382430.1	ENSP00000497822	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16003 AN: 152050 Hom.: 1506 Cov.: 33

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0699

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.0894 AC: 100813 AN: 1128126 Hom.: 7689 AF XY: 0.0896 AC XY: 49665 AN XY: 554096

Gnomad4 AFR exome AF: 0.0706

Gnomad4 AMR exome AF: 0.253

Gnomad4 ASJ exome AF: 0.0663

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0692

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.105 AC: 16001 AN: 152168 Hom.: 1503 Cov.: 33 AF XY: 0.111 AC XY: 8261 AN XY: 74366

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.0560

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.0976

Gnomad4 NFE AF: 0.0699

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0763 Hom.: 731

Bravo AF: 0.112

Asia WGS AF: 0.323 AC: 1119 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2494738; hg19: chr14-105246686; COSMIC: COSV62573162; COSMIC: COSV62573162;