14-104776629-T-C

Variant names:

• chr14-104776629-T-C
• rs2494735
• NM_001382430.1:c.287+30A>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.287+30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,598,064 control chromosomes in the GnomAD database, including 134,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20070 hom., cov: 34)
  • Exomes 𝑓: 0.38 (113999 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.66
• Publications: 16 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=-0.94).
• BP6: Variant 14-104776629-T-C is Benign according to our data. Variant chr14-104776629-T-C is described in ClinVar as Benign. ClinVar VariationId is 1272355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.287+30A>G		intron_variant	Intron 5 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.287+30A>G		intron_variant	Intron 5 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74300 AN: 152076 Hom.: 20042 Cov.: 34

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.463

GnomAD2 exomes AF: 0.459 AC: 111614 AN: 242980 AF XY: 0.448

Gnomad AFR exome AF: 0.709

Gnomad AMR exome AF: 0.585

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.646

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.385 AC: 556308 AN: 1445870 Hom.: 113999 Cov.: 27 AF XY: 0.387 AC XY: 278124 AN XY: 719302

African (AFR) AF: 0.722 AC: 23968 AN: 33214

American (AMR) AF: 0.574 AC: 25343 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8414 AN: 25710

East Asian (EAS) AF: 0.619 AC: 24433 AN: 39460

South Asian (SAS) AF: 0.530 AC: 45341 AN: 85502

European-Finnish (FIN) AF: 0.404 AC: 20850 AN: 51592

Middle Eastern (MID) AF: 0.444 AC: 2544 AN: 5726

European-Non Finnish (NFE) AF: 0.346 AC: 380763 AN: 1100744

Other (OTH) AF: 0.413 AC: 24652 AN: 59754

GnomAD4 genome AF: 0.489 AC: 74384 AN: 152194 Hom.: 20070 Cov.: 34 AF XY: 0.492 AC XY: 36600 AN XY: 74402

African (AFR) AF: 0.706 AC: 29303 AN: 41516

American (AMR) AF: 0.520 AC: 7955 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1134 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3345 AN: 5178

South Asian (SAS) AF: 0.578 AC: 2791 AN: 4832

European-Finnish (FIN) AF: 0.404 AC: 4280 AN: 10594

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24116 AN: 67984

Other (OTH) AF: 0.465 AC: 981 AN: 2110

Alfa AF: 0.417 Hom.: 2691

Bravo AF: 0.506

Asia WGS AF: 0.628 AC: 2184 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	-0.94
CADD	Benign	0.014
DANN	Benign	0.18
PhyloP100		-3.7
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)		0.0		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: rs2494735; hg19: chr14-105242966; COSMIC: COSV62573175; COSMIC: COSV62573175;