14-104772809-C-G

Position:

• chr14-104772809-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382430.1(AKT1):​c.1172+69G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,504,962 control chromosomes in the GnomAD database, including 49,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4572 hom., cov: 33)
  • Exomes 𝑓: 0.25 (45141 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.396

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-104772809-C-G is Benign according to our data. Variant chr14-104772809-C-G is described in ClinVar as [Benign]. Clinvar id is 1281623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1	c.1172+69G>C		intron_variant		ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2	c.1172+69G>C		intron_variant			NM_001382430.1	P1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36437 AN: 151674 Hom.: 4568 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0979

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.255 AC: 344850 AN: 1353172 Hom.: 45141 AF XY: 0.256 AC XY: 171210 AN XY: 667556

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.240 AC: 36471 AN: 151790 Hom.: 4572 Cov.: 33 AF XY: 0.241 AC XY: 17907 AN XY: 74156

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.0980

Gnomad4 SAS AF: 0.312

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.232

Alfa AF: 0.245 Hom.: 580

Bravo AF: 0.233

Asia WGS AF: 0.203 AC: 709 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.82
CADD	Benign	1.0
DANN	Benign	0.89

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: rs3803304; hg19: chr14-105239146; COSMIC: COSV62576115; COSMIC: COSV62576115;