NM_001382430.1:c.436-32C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001382430.1(AKT1):c.436-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,611,036 control chromosomes in the GnomAD database, including 3,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 1565 hom., cov: 33)

Exomes 𝑓: 0.014 ( 1520 hom. )

Consequence

AKT1
NM_001382430.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.46

Publications

9 publications found

Variant links:

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)

AKT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 14-104775239-G-A is Benign according to our data. Variant chr14-104775239-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1 link	c.436-32C>T		intron_variant	Intron 6 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2 link	c.436-32C>T		intron_variant	Intron 6 of 14		NM_001382430.1	ENSP00000497822.1		P31749-1

Frequencies

GnomAD3 genomes

AF:

0.0834

AC:

12691

AN:

152100

Hom.:

1563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0495

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00434

Gnomad OTH

AF:

0.0669

GnomAD2 exomes

AF:

0.0322

AC:

7974

AN:

247580

AF XY:

0.0264

show subpopulations

Gnomad AFR exome

AF:

0.276

Gnomad AMR exome

AF:

0.0446

Gnomad ASJ exome

AF:

0.00848

Gnomad EAS exome

AF:

0.0122

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.0226

GnomAD4 exome

AF:

0.0142

AC:

20762

AN:

1458818

Hom.:

1520

Cov.:

AF XY:

0.0136

AC XY:

9868

AN XY:

725886

show subpopulations

African (AFR)

AF:

0.280

AC:

9376

AN:

33472

American (AMR)

AF:

0.0451

AC:

2017

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00896

AC:

234

AN:

26128

East Asian (EAS)

AF:

0.0140

AC:

557

AN:

39698

South Asian (SAS)

AF:

0.0238

AC:

2049

AN:

86242

European-Finnish (FIN)

AF:

0.00971

AC:

491

AN:

50582

Middle Eastern (MID)

AF:

0.0290

AC:

167

AN:

5764

European-Non Finnish (NFE)

AF:

0.00393

AC:

4366

AN:

1111864

Other (OTH)

AF:

0.0249

AC:

1505

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1008

2016

3024

4032

5040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

396

792

1188

1584

1980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0836

AC:

12725

AN:

152218

Hom.:

1565

Cov.:

AF XY:

0.0821

AC XY:

6110

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.270

AC:

11190

AN:

41488

American (AMR)

AF:

0.0497

AC:

760

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.0140

AC:

AN:

5160

South Asian (SAS)

AF:

0.0240

AC:

116

AN:

4826

European-Finnish (FIN)

AF:

0.0112

AC:

119

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00434

AC:

295

AN:

68028

Other (OTH)

AF:

0.0662

AC:

140

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

481

963

1444

1926

2407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0403

Hom.:

239

Bravo

AF:

0.0960

Asia WGS

AF:

0.0400

AC:

138

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 03, 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

-0.93

CADD

Benign

0.019

(source)

DANN

Benign

0.63

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over