rs1130233

chr14-104773557-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001382430.1(AKT1):c.726G>A(p.Glu242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,607,306 control chromosomes in the GnomAD database, including 56,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5036 hom., cov: 33)
  • Exomes 𝑓: 0.26 (51921 hom.)
• Consequence: AKT1 NM_001382430.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.783

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-104773557-C-T is Benign according to our data. Variant chr14-104773557-C-T is described in ClinVar as [Benign]. Clinvar id is 498670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104773557-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.783 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1	c.726G>A	p.Glu242=	synonymous_variant	10/15	ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2	c.726G>A	p.Glu242=	synonymous_variant	10/15		NM_001382430.1	P1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35521 AN: 152108 Hom.: 5040 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.298 AC: 70714 AN: 237660 Hom.: 12365 AF XY: 0.294 AC XY: 37848 AN XY: 128602

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.580

Gnomad SAS exome AF: 0.325

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.257 AC: 373946 AN: 1455080 Hom.: 51921 Cov.: 38 AF XY: 0.258 AC XY: 186858 AN XY: 723270

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.326

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.233 AC: 35518 AN: 152226 Hom.: 5036 Cov.: 33 AF XY: 0.241 AC XY: 17961 AN XY: 74430

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.238

Alfa AF: 0.236 Hom.: 3386

Bravo AF: 0.236

Asia WGS AF: 0.426 AC: 1481 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cowden syndrome 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

This variant is associated with the following publications: (PMID: 18497887, 20520724) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	13
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1130233; hg19: chr14-105239894; COSMIC: COSV62571655; COSMIC: COSV62571655;