chr14-104780292-G-A

Variant names:

• chr14-104780292-G-A
• rs3730368
• NM_001382430.1:c.47-76C>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.47-76C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00695 in 1,570,916 control chromosomes in the GnomAD database, including 682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (366 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (316 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0670
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-104780292-G-A is Benign according to our data. Variant chr14-104780292-G-A is described in ClinVar as Benign. ClinVar VariationId is 1174307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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.47-76C>T		intron	N/A	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.47-76C>T		intron	N/A	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.47-76C>T		intron	N/A	NP_001014432.1	P31749-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.47-76C>T		intron	N/A	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.47-76C>T		intron	N/A	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.47-76C>T		intron	N/A	ENSP00000385326.2	P31749-1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5631 AN: 152154 Hom.: 367 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00372 AC: 5282 AN: 1418644 Hom.: 316 AF XY: 0.00320 AC XY: 2245 AN XY: 701768

African (AFR) AF: 0.134 AC: 4374 AN: 32628

American (AMR) AF: 0.00633 AC: 268 AN: 42332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24358

East Asian (EAS) AF: 0.00 AC: 0 AN: 38404

South Asian (SAS) AF: 0.000309 AC: 25 AN: 80896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46658

Middle Eastern (MID) AF: 0.00501 AC: 28 AN: 5584

European-Non Finnish (NFE) AF: 0.000118 AC: 128 AN: 1089190

Other (OTH) AF: 0.00783 AC: 459 AN: 58594

GnomAD4 genome AF: 0.0370 AC: 5634 AN: 152272 Hom.: 366 Cov.: 33 AF XY: 0.0359 AC XY: 2677 AN XY: 74472

African (AFR) AF: 0.130 AC: 5398 AN: 41532

American (AMR) AF: 0.0111 AC: 170 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68014

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0267 Hom.: 28

Bravo AF: 0.0411

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.8
DANN	Benign	0.86
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3730368; hg19: chr14-105246629; COSMIC: COSV104422014;