rs2498801

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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]

AKT1 Gene-Disease associations (from GenCC):

• Proteus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 6

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649815.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	NM_001382430.1	MANE Select	c.*1120A>G		downstream_gene	N/A	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.*1120A>G		downstream_gene	N/A	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.*1120A>G		downstream_gene	N/A	NP_001014432.1	P31749-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.*1120A>G		downstream_gene	N/A	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.*1120A>G		downstream_gene	N/A	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.*1120A>G		downstream_gene	N/A	ENSP00000385326.2	P31749-1

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

African (AFR) AF: 0.456 AC: 729 AN: 1600

American (AMR) AF: 0.484 AC: 624 AN: 1288

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 805 AN: 2614

East Asian (EAS) AF: 0.572 AC: 4140 AN: 7240

South Asian (SAS) AF: 0.491 AC: 397 AN: 808

European-Finnish (FIN) AF: 0.375 AC: 27 AN: 72

Middle Eastern (MID) AF: 0.357 AC: 97 AN: 272

European-Non Finnish (NFE) AF: 0.343 AC: 9132 AN: 26626

Other (OTH) AF: 0.370 AC: 1308 AN: 3532

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

African (AFR) AF: 0.471 AC: 19517 AN: 41470

American (AMR) AF: 0.473 AC: 7229 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1068 AN: 3470

East Asian (EAS) AF: 0.632 AC: 3257 AN: 5152

South Asian (SAS) AF: 0.542 AC: 2608 AN: 4812

European-Finnish (FIN) AF: 0.372 AC: 3940 AN: 10580

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23447 AN: 67942

Other (OTH) AF: 0.400 AC: 845 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.41
PhyloP100		-1.2

Splicing

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

Other links and lift over

dbSNP: rs2498801; hg19: chr14-105235558;