14-104776629-T-C

Position:

• chr14-104776629-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001382430.1(AKT1):​c.287+30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,598,064 control chromosomes in the GnomAD database, including 134,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (20070 hom., cov: 34)
  • Exomes 𝑓: 0.38 (113999 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.66

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-104776629-T-C is Benign according to our data. Variant chr14-104776629-T-C is described in ClinVar as [Benign]. Clinvar id is 1272355.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-104776629-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1	c.287+30A>G		intron_variant		ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2	c.287+30A>G		intron_variant			NM_001382430.1	P1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74300 AN: 152076 Hom.: 20042 Cov.: 34

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.459 AC: 111614 AN: 242980 Hom.: 27735 AF XY: 0.448 AC XY: 58937 AN XY: 131632

Gnomad AFR exome AF: 0.709

Gnomad AMR exome AF: 0.585

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.385 AC: 556308 AN: 1445870 Hom.: 113999 Cov.: 27 AF XY: 0.387 AC XY: 278124 AN XY: 719302

Gnomad4 AFR exome AF: 0.722

Gnomad4 AMR exome AF: 0.574

Gnomad4 ASJ exome AF: 0.327

Gnomad4 EAS exome AF: 0.619

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.489 AC: 74384 AN: 152194 Hom.: 20070 Cov.: 34 AF XY: 0.492 AC XY: 36600 AN XY: 74402

Gnomad4 AFR AF: 0.706

Gnomad4 AMR AF: 0.520

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.578

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.465

Alfa AF: 0.417 Hom.: 2691

Bravo AF: 0.506

Asia WGS AF: 0.628 AC: 2184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.014
DANN	Benign	0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2494735; hg19: chr14-105242966; COSMIC: COSV62573175; COSMIC: COSV62573175;