14-104772951-G-T

Position:

• chr14-104772951-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

The NM_001382430.1(AKT1):​c.1099C>A​(p.Arg367Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (1 hom.)
• Consequence: AKT1 NM_001382430.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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=0.20609513).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000171 (25/1461804) while in subpopulation SAS AF= 0.00029 (25/86254). AF 95% confidence interval is 0.000201. There are 1 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.1099C>A	p.Arg367Ser	missense_variant	12/15	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.1099C>A	p.Arg367Ser	missense_variant	12/15		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251334 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461804 Hom.: 1 Cov.: 36 AF XY: 0.0000193 AC XY: 14 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cowden syndrome 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with AKT1-related disease. This variant is present in population databases (rs762705090, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces arginine with serine at codon 367 of the AKT1 protein (p.Arg367Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;D;D;D;D;D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	.;.;.;.;.;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L;L;L;L;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D;D;D;D;D;.;D
REVEL	Benign	0.20
Sift	Benign	0.068	T;T;T;T;T;.;T
Sift4G	Benign	0.25	T;T;T;T;T;.;T
Polyphen		0.15	B;B;B;B;B;B;B
Vest4		0.66
MutPred		0.45		Gain of catalytic residue at T371 (P = 0.0146);Gain of catalytic residue at T371 (P = 0.0146);Gain of catalytic residue at T371 (P = 0.0146);Gain of catalytic residue at T371 (P = 0.0146);Gain of catalytic residue at T371 (P = 0.0146);Gain of catalytic residue at T371 (P = 0.0146);Gain of catalytic residue at T371 (P = 0.0146);
MVP		0.60
MPC		1.4
ClinPred		0.58	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.81

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

Other links and lift over

dbSNP: rs762705090; hg19: chr14-105239288;