NM_001382430.1:c.287+70C>T

Variant names:

• chr14-104776589-G-A
• rs17846822
• NM_001382430.1:c.287+70C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001382430.1(AKT1):​c.287+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,366,040 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0032 (50 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.07

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00225 (343/152320) while in subpopulation SAS AF= 0.0271 (131/4828). AF 95% confidence interval is 0.0234. There are 2 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.287+70C>T		intron_variant	Intron 5 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.287+70C>T		intron_variant	Intron 5 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152202 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00316 AC: 3837 AN: 1213720 Hom.: 50 Cov.: 16 AF XY: 0.00376 AC XY: 2277 AN XY: 605772

Gnomad4 AFR exome AF: 0.000323

Gnomad4 AMR exome AF: 0.000424

Gnomad4 ASJ exome AF: 0.00285

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.0245

Gnomad4 FIN exome AF: 0.0000450

Gnomad4 NFE exome AF: 0.000798

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152320 Hom.: 2 Cov.: 34 AF XY: 0.00273 AC XY: 203 AN XY: 74478

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0176

Gnomad4 SAS AF: 0.0271

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.00190

Asia WGS AF: 0.0330 AC: 114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs17846822; hg19: chr14-105242926;