NM_001382430.1:c.726G>A

Variant names:

• chr14-104773557-C-T
• rs1130233
• NM_001382430.1:c.726G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001382430.1(AKT1):​c.726G>A​(p.Glu242Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,607,306 control chromosomes in the GnomAD database, including 56,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5036 hom., cov: 33)
  • Exomes 𝑓: 0.26 (51921 hom.)
• Consequence: AKT1 NM_001382430.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.783
• Publications: 122 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-104773557-C-T is Benign according to our data. Variant chr14-104773557-C-T is described in ClinVar as Benign. ClinVar VariationId is 498670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.783 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 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.726G>A	p.Glu242Glu	synonymous	Exon 10 of 15	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.726G>A	p.Glu242Glu	synonymous	Exon 9 of 14	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.726G>A	p.Glu242Glu	synonymous	Exon 10 of 15	NP_001014432.1	P31749-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.726G>A	p.Glu242Glu	synonymous	Exon 10 of 15	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.726G>A	p.Glu242Glu	synonymous	Exon 10 of 15	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.726G>A	p.Glu242Glu	synonymous	Exon 9 of 14	ENSP00000385326.2	P31749-1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35521 AN: 152108 Hom.: 5040 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.298 AC: 70714 AN: 237660 AF XY: 0.294

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.580

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.257 AC: 373946 AN: 1455080 Hom.: 51921 Cov.: 38 AF XY: 0.258 AC XY: 186858 AN XY: 723270

African (AFR) AF: 0.105 AC: 3526 AN: 33430

American (AMR) AF: 0.454 AC: 19684 AN: 43358

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5693 AN: 25912

East Asian (EAS) AF: 0.527 AC: 20729 AN: 39340

South Asian (SAS) AF: 0.326 AC: 27770 AN: 85214

European-Finnish (FIN) AF: 0.246 AC: 12970 AN: 52710

Middle Eastern (MID) AF: 0.222 AC: 1275 AN: 5746

European-Non Finnish (NFE) AF: 0.241 AC: 266948 AN: 1109222

Other (OTH) AF: 0.255 AC: 15351 AN: 60148

GnomAD4 genome AF: 0.233 AC: 35518 AN: 152226 Hom.: 5036 Cov.: 33 AF XY: 0.241 AC XY: 17961 AN XY: 74430

African (AFR) AF: 0.110 AC: 4571 AN: 41546

American (AMR) AF: 0.370 AC: 5666 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3472

East Asian (EAS) AF: 0.580 AC: 3000 AN: 5172

South Asian (SAS) AF: 0.366 AC: 1770 AN: 4832

European-Finnish (FIN) AF: 0.253 AC: 2686 AN: 10612

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16285 AN: 67982

Other (OTH) AF: 0.238 AC: 503 AN: 2110

Alfa AF: 0.234 Hom.: 4270

Bravo AF: 0.236

Asia WGS AF: 0.426 AC: 1481 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Cowden syndrome 6 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		0.78
PromoterAI		0.0033	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1130233; hg19: chr14-105239894; COSMIC: COSV62571655; COSMIC: COSV62571655;