rs1130233

Positions:

chr14-104773557-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.783

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
AKT1	NM_001382430.1 linkuse as main transcript	c.726G>A	p.Glu242=	synonymous_variant	10/15	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2 linkuse as main transcript	c.726G>A	p.Glu242=	synonymous_variant	10/15		NM_001382430.1	ENSP00000497822	P1	P31749-1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35521

AN:

152108

Hom.:

5040

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.258

AC XY:

186858

AN XY:

723270

show subpopulations

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.:

AF XY:

0.241

AC XY:

17961

AN XY:

74430

show subpopulations

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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	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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over