14-104780125-G-T

Position:

chr14-104780125-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBP6BS1

The NM_001382430.1(AKT1):c.138C>A(p.Asp46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,613,688 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

AKT1
NM_001382430.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: 2.59

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 Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AKT1. . Gene score misZ 3.4778 (greater than the threshold 3.09). Trascript score misZ 4.2155 (greater than threshold 3.09). GenCC has associacion of gene with Proteus syndrome, Cowden disease, Cowden syndrome 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.050059468).

BP6

Variant 14-104780125-G-T is Benign according to our data. Variant chr14-104780125-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133455.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, not_provided=1}. Variant chr14-104780125-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000433 (66/152334) while in subpopulation AMR AF= 0.00137 (21/15304). AF 95% confidence interval is 0.000919. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT1	NM_001382430.1 linkuse as main transcript	c.138C>A	p.Asp46Glu	missense_variant	4/15	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.138C>A	p.Asp46Glu	missense_variant	4/15		NM_001382430.1	ENSP00000497822	P1	P31749-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000327

AC:

AN:

250802

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000406

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000500

AC:

730

AN:

1461354

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

346

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000589

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000433

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000439

Hom.:

Bravo

AF:

0.000616

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with familial hypercholesterolemia (Marmontel et al., 2020); This variant is associated with the following publications: (PMID: 33111339, 33916788) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	AKT1: BP4, BS1 -

Cowden syndrome 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

AKT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;D;D;D;D;D;D;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.66

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

.;.;.;.;.;.;T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.050

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.94

L;L;L;L;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.3

N;N;N;N;N;.;N;N

REVEL

Benign

0.17

Sift

Benign

0.22

T;T;T;T;T;.;T;T

Sift4G

Benign

0.26

T;T;T;T;T;.;T;.

Polyphen

0.055

B;B;B;B;B;B;B;.

Vest4

0.21

MutPred

0.42

Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);Gain of catalytic residue at P42 (P = 0.0582);

MVP

0.53

MPC

0.90

ClinPred

0.041

GERP RS

-1.9

Varity_R

0.29

gMVP

0.36

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