Variant rs3730358 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001382430.1(AKT1):c.175+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,610,612 control chromosomes in the GnomAD database, including 19,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2164 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17769 hom. )

Consequence

AKT1
NM_001382430.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.87

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 14-104780070-G-A is Benign according to our data. Variant chr14-104780070-G-A is described in ClinVar as [Benign]. Clinvar id is 1284750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104780070-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 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.175+18C>T		intron_variant		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.175+18C>T		intron_variant			NM_001382430.1	ENSP00000497822	P1	P31749-1

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25420

AN:

152120

Hom.:

2164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.0675

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.162

GnomAD3 exomes

AF:

0.160

AC:

39847

AN:

249250

Hom.:

3567

AF XY:

0.160

AC XY:

21589

AN XY:

134964

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.233

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.0630

Gnomad SAS exome

AF:

0.189

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.147

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.153

AC:

223110

AN:

1458374

Hom.:

17769

Cov.:

AF XY:

0.154

AC XY:

111748

AN XY:

725196

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.158

Gnomad4 EAS exome

AF:

0.0867

Gnomad4 SAS exome

AF:

0.189

Gnomad4 FIN exome

AF:

0.119

Gnomad4 NFE exome

AF:

0.149

Gnomad4 OTH exome

AF:

0.149

GnomAD4 genome

AF:

0.167

AC:

25426

AN:

152238

Hom.:

2164

Cov.:

AF XY:

0.166

AC XY:

12363

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.204

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.0676

Gnomad4 SAS

AF:

0.187

Gnomad4 FIN

AF:

0.128

Gnomad4 NFE

AF:

0.150

Gnomad4 OTH

AF:

0.161

Alfa

AF:

0.122

Hom.:

420

Bravo

AF:

0.176

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.14

DANN

Benign

0.29

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

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