14-104771343-G-C

Variant names:

• chr14-104771343-G-C
• rs2494731
• NM_001382430.1:c.1261-496C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001382430.1(AKT1):​c.1261-496C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 241,766 control chromosomes in the GnomAD database, including 19,989 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (13041 hom., cov: 32)
  • Exomes 𝑓: 0.38 (6948 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.75
• Publications: 27 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.1261-496C>G		intron_variant	Intron 13 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.1261-496C>G		intron_variant	Intron 13 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61665 AN: 151792 Hom.: 13033 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.394

GnomAD4 exome AF: 0.380 AC: 34114 AN: 89856 Hom.: 6948 Cov.: 0 AF XY: 0.379 AC XY: 15968 AN XY: 42154

African (AFR) AF: 0.459 AC: 1803 AN: 3928

American (AMR) AF: 0.462 AC: 1756 AN: 3798

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1539 AN: 5122

East Asian (EAS) AF: 0.572 AC: 6555 AN: 11454

South Asian (SAS) AF: 0.463 AC: 948 AN: 2048

European-Finnish (FIN) AF: 0.314 AC: 118 AN: 376

Middle Eastern (MID) AF: 0.348 AC: 181 AN: 520

European-Non Finnish (NFE) AF: 0.335 AC: 18565 AN: 55444

Other (OTH) AF: 0.370 AC: 2649 AN: 7166

GnomAD4 genome AF: 0.406 AC: 61721 AN: 151910 Hom.: 13041 Cov.: 32 AF XY: 0.411 AC XY: 30512 AN XY: 74256

African (AFR) AF: 0.465 AC: 19251 AN: 41390

American (AMR) AF: 0.471 AC: 7199 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3464

East Asian (EAS) AF: 0.630 AC: 3238 AN: 5140

South Asian (SAS) AF: 0.547 AC: 2635 AN: 4818

European-Finnish (FIN) AF: 0.371 AC: 3927 AN: 10574

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23212 AN: 67930

Other (OTH) AF: 0.396 AC: 834 AN: 2106

Alfa AF: 0.378 Hom.: 1439

Bravo AF: 0.414

Asia WGS AF: 0.587 AC: 2041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.29
DANN	Benign	0.63
PhyloP100		-3.7
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: rs2494731; hg19: chr14-105237680;