rs2494738

Variant names:

• chr14-104780349-G-A
• rs2494738
• NM_001382430.1:c.47-133C>T

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.47-133C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,280,294 control chromosomes in the GnomAD database, including 9,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1503 hom., cov: 33)
  • Exomes 𝑓: 0.089 (7689 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14
• Publications: 45 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=-0.91).
• BP6: Variant 14-104780349-G-A is Benign according to our data. Variant chr14-104780349-G-A is described in ClinVar as Benign. ClinVar VariationId is 1281679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.47-133C>T		intron_variant	Intron 3 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.47-133C>T		intron_variant	Intron 3 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16003 AN: 152050 Hom.: 1506 Cov.: 33

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0699

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.0894 AC: 100813 AN: 1128126 Hom.: 7689 AF XY: 0.0896 AC XY: 49665 AN XY: 554096

African (AFR) AF: 0.0706 AC: 1775 AN: 25134

American (AMR) AF: 0.253 AC: 5933 AN: 23476

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 1210 AN: 18262

East Asian (EAS) AF: 0.443 AC: 14599 AN: 32936

South Asian (SAS) AF: 0.124 AC: 7586 AN: 61284

European-Finnish (FIN) AF: 0.102 AC: 3155 AN: 30894

Middle Eastern (MID) AF: 0.0712 AC: 281 AN: 3946

European-Non Finnish (NFE) AF: 0.0692 AC: 61207 AN: 884364

Other (OTH) AF: 0.106 AC: 5067 AN: 47830

GnomAD4 genome AF: 0.105 AC: 16001 AN: 152168 Hom.: 1503 Cov.: 33 AF XY: 0.111 AC XY: 8261 AN XY: 74366

African (AFR) AF: 0.0761 AC: 3160 AN: 41536

American (AMR) AF: 0.201 AC: 3063 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 194 AN: 3466

East Asian (EAS) AF: 0.514 AC: 2654 AN: 5160

South Asian (SAS) AF: 0.167 AC: 807 AN: 4822

European-Finnish (FIN) AF: 0.0976 AC: 1034 AN: 10598

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0699 AC: 4754 AN: 68000

Other (OTH) AF: 0.106 AC: 224 AN: 2106

Alfa AF: 0.0777 Hom.: 1121

Bravo AF: 0.112

Asia WGS AF: 0.323 AC: 1119 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.59
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2494738; hg19: chr14-105246686; COSMIC: COSV62573162; COSMIC: COSV62573162;