rs2494732

Variant names:

• chr14-104772855-T-C
• rs2494732
• NM_001382430.1:c.1172+23A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-104772855-T-C
• chr14-104772855-T-A
• chr14-104772855-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.1172+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 1,592,622 control chromosomes in the GnomAD database, including 167,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17643 hom., cov: 33)
  • Exomes 𝑓: 0.45 (149509 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.61
• Publications: 110 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, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 14-104772855-T-C is Benign according to our data. Variant chr14-104772855-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382430.1. 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.1172+23A>G		intron	N/A	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.1172+23A>G		intron	N/A	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.1172+23A>G		intron	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.1172+23A>G		intron	N/A	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.1172+23A>G		intron	N/A	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.1172+23A>G		intron	N/A	ENSP00000385326.2	P31749-1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72230 AN: 151832 Hom.: 17628 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.499 AC: 114234 AN: 229088 AF XY: 0.492

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.625

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.730

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.450 AC: 648878 AN: 1440672 Hom.: 149509 Cov.: 38 AF XY: 0.452 AC XY: 323372 AN XY: 715580

African (AFR) AF: 0.490 AC: 16303 AN: 33256

American (AMR) AF: 0.614 AC: 26579 AN: 43294

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10655 AN: 25730

East Asian (EAS) AF: 0.700 AC: 27487 AN: 39262

South Asian (SAS) AF: 0.545 AC: 46444 AN: 85168

European-Finnish (FIN) AF: 0.436 AC: 19631 AN: 44996

Middle Eastern (MID) AF: 0.431 AC: 1902 AN: 4412

European-Non Finnish (NFE) AF: 0.427 AC: 472085 AN: 1104892

Other (OTH) AF: 0.466 AC: 27792 AN: 59662

GnomAD4 genome AF: 0.476 AC: 72298 AN: 151950 Hom.: 17643 Cov.: 33 AF XY: 0.480 AC XY: 35651 AN XY: 74266

African (AFR) AF: 0.492 AC: 20373 AN: 41440

American (AMR) AF: 0.552 AC: 8437 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1464 AN: 3466

East Asian (EAS) AF: 0.722 AC: 3713 AN: 5144

South Asian (SAS) AF: 0.598 AC: 2887 AN: 4824

European-Finnish (FIN) AF: 0.437 AC: 4616 AN: 10572

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29377 AN: 67904

Other (OTH) AF: 0.473 AC: 998 AN: 2110

Alfa AF: 0.453 Hom.: 33669

Bravo AF: 0.484

Asia WGS AF: 0.656 AC: 2279 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.40
DANN	Benign	0.55
PhyloP100		-4.6
PromoterAI		-0.020	Neutral
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: rs2494732; hg19: chr14-105239192; COSMIC: COSV62573275;