rs2494737

Variant names:

• chr14-104779988-T-A
• rs2494737
• NM_001382430.1:c.175+100A>T

Your query was ambiguous. Multiple possible variants found:

• chr14-104779988-T-A
• chr14-104779988-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382430.1(AKT1):​c.175+100A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,502,850 control chromosomes in the GnomAD database, including 94,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13279 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81205 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.09
• Publications: 18 publications found

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]

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 Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-104779988-T-A is Benign according to our data. Variant chr14-104779988-T-A is described in ClinVar as Benign. ClinVar VariationId is 695299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.175+100A>T		intron_variant	Intron 4 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.175+100A>T		intron_variant	Intron 4 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61425 AN: 151962 Hom.: 13265 Cov.: 33

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.334 AC: 451706 AN: 1350770 Hom.: 81205 AF XY: 0.338 AC XY: 224650 AN XY: 665046

African (AFR) AF: 0.514 AC: 15550 AN: 30260

American (AMR) AF: 0.542 AC: 18076 AN: 33346

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 6479 AN: 21068

East Asian (EAS) AF: 0.617 AC: 23525 AN: 38158

South Asian (SAS) AF: 0.495 AC: 36372 AN: 73536

European-Finnish (FIN) AF: 0.351 AC: 15036 AN: 42798

Middle Eastern (MID) AF: 0.389 AC: 1668 AN: 4292

European-Non Finnish (NFE) AF: 0.299 AC: 314974 AN: 1051800

Other (OTH) AF: 0.361 AC: 20026 AN: 55512

GnomAD4 genome AF: 0.404 AC: 61484 AN: 152080 Hom.: 13279 Cov.: 33 AF XY: 0.411 AC XY: 30532 AN XY: 74332

African (AFR) AF: 0.511 AC: 21217 AN: 41484

American (AMR) AF: 0.477 AC: 7295 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1053 AN: 3472

East Asian (EAS) AF: 0.639 AC: 3301 AN: 5166

South Asian (SAS) AF: 0.543 AC: 2609 AN: 4804

European-Finnish (FIN) AF: 0.355 AC: 3759 AN: 10592

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21053 AN: 67954

Other (OTH) AF: 0.398 AC: 838 AN: 2108

Alfa AF: 0.367 Hom.: 1368

Bravo AF: 0.418

Asia WGS AF: 0.591 AC: 2053 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27259051) -

Cowden syndrome 6 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.30
DANN	Benign	0.51
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2494737; hg19: chr14-105246325; COSMIC: COSV62575435; COSMIC: COSV62575435;