14-104776721-G-C

Position:

• chr14-104776721-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BS1_Supporting

The NM_001382430.1(AKT1):​c.225C>G​(p.Ile75Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: AKT1 NM_001382430.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.55

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 2 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.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000684 (10/1461140) while in subpopulation EAS AF= 0.000252 (10/39696). AF 95% confidence interval is 0.000136. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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.225C>G	p.Ile75Met	missense_variant	5/15	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.225C>G	p.Ile75Met	missense_variant	5/15		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250848 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461140 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other: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

Jun 07, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 133456). This variant has not been reported in the literature in individuals affected with AKT1-related conditions. This variant is present in population databases (rs587778019, gnomAD 0.03%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 75 of the AKT1 protein (p.Ile75Met). -

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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D;D;D;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.067	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N;N;N;N;N;.;N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.016	D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;.;D;.
Polyphen		1.0	D;D;D;D;D;D;D;.
Vest4		0.73
MutPred		0.62		Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);Gain of catalytic residue at I75 (P = 0);
MVP		0.92
MPC		2.0
ClinPred		0.82	D
GERP RS		0.43
Varity_R		0.72
gMVP		0.90

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: rs587778019; hg19: chr14-105243058;