rs2230506

Variant names:

• chr14-104774967-G-A
• rs2230506
• NM_001382430.1:c.604C>T
• AKT1 p.Leu202Leu

Your query was ambiguous. Multiple possible variants found:

• chr14-104774967-G-A
• chr14-104774967-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001382430.1(AKT1):​c.604C>T​(p.Leu202Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,612,822 control chromosomes in the GnomAD database, including 676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L202L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (337 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (339 hom.)
• Consequence: AKT1 NM_001382430.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.04
• Publications: 8 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 -16 ACMG points.

• BP6: Variant 14-104774967-G-A is Benign according to our data. Variant chr14-104774967-G-A is described in ClinVar as Benign. ClinVar VariationId is 416469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 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.604C>T	p.Leu202Leu	synonymous	Exon 8 of 15	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.604C>T	p.Leu202Leu	synonymous	Exon 7 of 14	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.604C>T	p.Leu202Leu	synonymous	Exon 8 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.604C>T	p.Leu202Leu	synonymous	Exon 8 of 15	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.604C>T	p.Leu202Leu	synonymous	Exon 8 of 15	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.604C>T	p.Leu202Leu	synonymous	Exon 7 of 14	ENSP00000385326.2	P31749-1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5461 AN: 151982 Hom.: 337 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.00969 AC: 2425 AN: 250248 AF XY: 0.00707

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.00666

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000330

Gnomad NFE exome AF: 0.000637

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00396 AC: 5791 AN: 1460722 Hom.: 339 Cov.: 31 AF XY: 0.00346 AC XY: 2513 AN XY: 726678

African (AFR) AF: 0.132 AC: 4407 AN: 33476

American (AMR) AF: 0.00770 AC: 344 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86232

European-Finnish (FIN) AF: 0.000247 AC: 13 AN: 52626

Middle Eastern (MID) AF: 0.0118 AC: 67 AN: 5682

European-Non Finnish (NFE) AF: 0.000342 AC: 380 AN: 1111852

Other (OTH) AF: 0.00886 AC: 535 AN: 60358

GnomAD4 genome AF: 0.0359 AC: 5463 AN: 152100 Hom.: 337 Cov.: 33 AF XY: 0.0340 AC XY: 2531 AN XY: 74368

African (AFR) AF: 0.125 AC: 5169 AN: 41424

American (AMR) AF: 0.0123 AC: 188 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4810

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67994

Other (OTH) AF: 0.0261 AC: 55 AN: 2110

Alfa AF: 0.0167 Hom.: 87

Bravo AF: 0.0413

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000831

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.75
PhyloP100		3.0
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)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2230506;

hg19: chr14-105241304;

COSMIC: COSV104422011;