NM_001382430.1:c.1261-217T>C

Variant names:

• chr14-104771064-A-G
• rs7140735
• NM_001382430.1:c.1261-217T>C

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.1261-217T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.076 in 559,944 control chromosomes in the GnomAD database, including 1,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (473 hom., cov: 33)
  • Exomes 𝑓: 0.076 (1390 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.959
• Publications: 3 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=-0.85).
• BP6: Variant 14-104771064-A-G is Benign according to our data. Variant chr14-104771064-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.1261-217T>C		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.1261-217T>C		intron_variant	Intron 13 of 14		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.0764 AC: 11623 AN: 152200 Hom.: 472 Cov.: 33

Gnomad AFR AF: 0.0854

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0547

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.0812

GnomAD4 exome AF: 0.0758 AC: 30905 AN: 407626 Hom.: 1390 Cov.: 3 AF XY: 0.0769 AC XY: 16423 AN XY: 213520

African (AFR) AF: 0.0877 AC: 1022 AN: 11656

American (AMR) AF: 0.0414 AC: 683 AN: 16488

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 660 AN: 12734

East Asian (EAS) AF: 0.0432 AC: 1264 AN: 29234

South Asian (SAS) AF: 0.112 AC: 4254 AN: 38056

European-Finnish (FIN) AF: 0.120 AC: 3292 AN: 27452

Middle Eastern (MID) AF: 0.102 AC: 186 AN: 1820

European-Non Finnish (NFE) AF: 0.0719 AC: 17708 AN: 246184

Other (OTH) AF: 0.0765 AC: 1836 AN: 24002

GnomAD4 genome AF: 0.0764 AC: 11634 AN: 152318 Hom.: 473 Cov.: 33 AF XY: 0.0768 AC XY: 5721 AN XY: 74476

African (AFR) AF: 0.0854 AC: 3551 AN: 41574

American (AMR) AF: 0.0519 AC: 794 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 190 AN: 3472

East Asian (EAS) AF: 0.0282 AC: 146 AN: 5182

South Asian (SAS) AF: 0.117 AC: 564 AN: 4822

European-Finnish (FIN) AF: 0.108 AC: 1142 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0735 AC: 4999 AN: 68020

Other (OTH) AF: 0.0851 AC: 180 AN: 2116

Alfa AF: 0.0641 Hom.: 164

Bravo AF: 0.0704

Asia WGS AF: 0.0930 AC: 325 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

- -

Feb 28, 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	-0.85
CADD	Benign	1.1
DANN	Benign	0.84
PhyloP100		-0.96
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: rs7140735; hg19: chr14-105237401; COSMIC: COSV62572132; COSMIC: COSV62572132;