rs2498801

Variant names:

• chr14-104769221-T-C
• rs2498801
• XR_007064362.1:n.3441T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XR_429419.5(LOC102723342):​n.3057T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 196,072 control chromosomes in the GnomAD database, including 16,811 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 0.41 (13251 hom., cov: 33)
  • Exomes 𝑓: 0.39 (3560 hom.)
• Consequence: LOC102723342 XR_429419.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

Genes affected

LOC102723342 (HGNC:):

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.*1120A>G		downstream_gene_variant		ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.*1120A>G		downstream_gene_variant			NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62230 AN: 151904 Hom.: 13243 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.398

GnomAD4 exome AF: 0.392 AC: 17259 AN: 44052 Hom.: 3560 AF XY: 0.390 AC XY: 8149 AN XY: 20912

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.484

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.572

Gnomad4 SAS exome AF: 0.491

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.410 AC: 62285 AN: 152020 Hom.: 13251 Cov.: 33 AF XY: 0.414 AC XY: 30755 AN XY: 74300

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.308

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.345

Gnomad4 OTH AF: 0.400

Alfa AF: 0.384 Hom.: 1407

Bravo AF: 0.418

Asia WGS AF: 0.589 AC: 2048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.41

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2498801; hg19: chr14-105235558;