14-104772855-T-C

Variant names:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_001382430.1(AKT1):c.1172+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.453 (AC=721,176) in the gnomAD database across 1,592,622 control chromosomes, including 167,152 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.702. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17643 hom., cov: 33)

Exomes 𝑓: 0.45 ( 149509 hom. )

Consequence

AKT1
NM_001382430.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.61

Publications

111 publications found

Variant links:

COSMIC-nc: COSV62573275

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 6
Inheritance: AD, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

AKT1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001382430.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -16 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7024 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001382430.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AKT1	NM_001382430.1	MANE Select	c.1172+23A>G	intron	N/A	NP_001369359.1	P31749-1
AKT1	NM_001014431.2		c.1172+23A>G	intron	N/A	NP_001014431.1	B0LPE5
AKT1	NM_001014432.2		c.1172+23A>G	intron	N/A	NP_001014432.1	P31749-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AKT1	ENST00000649815.2	MANE Select	c.1172+23A>G	intron	N/A	ENSP00000497822.1	P31749-1
AKT1	ENST00000349310.7	TSL:1	c.1172+23A>G	intron	N/A	ENSP00000270202.4	P31749-1
AKT1	ENST00000402615.6	TSL:1	c.1172+23A>G	intron	N/A	ENSP00000385326.2	P31749-1

Frequencies

GnomAD3 genomes

AF:

0.476

AC:

72230

AN:

151832

Hom.:

17628

Cov.:

show subpopulations

Gnomad AFR

AF:

0.491

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.552

Gnomad ASJ

AF:

0.422

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.599

Gnomad FIN

AF:

0.437

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.433

Gnomad OTH

AF:

0.468

GnomAD2 exomes

AF:

0.499

AC:

114234

AN:

229088

AF XY:

0.492

show subpopulations

Gnomad AFR exome

AF:

0.490

Gnomad AMR exome

AF:

0.625

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.730

Gnomad FIN exome

AF:

0.427

Gnomad NFE exome

AF:

0.429

Gnomad OTH exome

AF:

0.467

GnomAD4 exome

AF:

0.450

AC:

648878

AN:

1440672

Hom.:

149509

Cov.:

AF XY:

0.452

AC XY:

323372

AN XY:

715580

show subpopulations

African (AFR)

AF:

0.490

AC:

16303

AN:

33256

American (AMR)

AF:

0.614

AC:

26579

AN:

43294

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

10655

AN:

25730

East Asian (EAS)

AF:

0.700

AC:

27487

AN:

39262

South Asian (SAS)

AF:

0.545

AC:

46444

AN:

85168

European-Finnish (FIN)

AF:

0.436

AC:

19631

AN:

44996

Middle Eastern (MID)

AF:

0.431

AC:

1902

AN:

4412

European-Non Finnish (NFE)

AF:

0.427

AC:

472085

AN:

1104892

Other (OTH)

AF:

0.466

AC:

27792

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

20745

41491

62236

82982

103727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14650

29300

43950

58600

73250

<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:

0.476

AC:

72298

AN:

151950

Hom.:

17643

Cov.:

AF XY:

0.480

AC XY:

35651

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.492

AC:

20373

AN:

41440

American (AMR)

AF:

0.552

AC:

8437

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.422

AC:

1464

AN:

3466

East Asian (EAS)

AF:

0.722

AC:

3713

AN:

5144

South Asian (SAS)

AF:

0.598

AC:

2887

AN:

4824

European-Finnish (FIN)

AF:

0.437

AC:

4616

AN:

10572

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.433

AC:

29377

AN:

67904

Other (OTH)

AF:

0.473

AC:

998

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1964

3929

5893

7858

9822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

662

1324

1986

2648

3310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.484

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.454

AC:

154175

AN:

339666

Hom.:

35473

Local populations

ABraOM SABE-WGS-1171

AF:

0.479

AC:

1121

AN:

2342

Hom.:

270

ChinaMAP Phase 1

AF:

0.727

Denmark Genome

AF:

0.440

AC:

132

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.453

AC:

5891

AN:

13004

show subpopulations

European American

AF:

0.437

AC:

3754

AN:

8598

African American

AF:

0.485

AC:

2137

AN:

4406

GenomeAsia100K

AF:

0.656

AC:

2279

AN:

3478

show subpopulations

Oceania

AF:

0.622

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.662

AC:

465

AN:

702

Hom.:

156

South-East Asia

AF:

0.743

AC:

514

AN:

692

Hom.:

190

South Asia

AF:

0.666

AC:

964

AN:

1448

Hom.:

338

Africa

AF:

0.534

AC:

111

AN:

208

Hom.:

America

AF:

0.769

AC:

AN:

Hom.:

West Eurasia

AF:

0.408

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.700

AC:

5059

AN:

7228

Qatari Genome

AF:

0.460

AC:

AN:

176

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.670

AC:

82033

AN:

122400

Hom.:

27552

Turkish Variome

AF:

0.429

AC:

2834

AN:

6608

Hom.:

632

UK10K

AF:

0.415

AC:

3136

AN:

7562

show subpopulations

TwinsUK

AF:

0.419

AC:

1499

AN:

3574

ALSPAC

AF:

0.410

AC:

1579

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.736

AC:

6595

AN:

8960

Hom.:

2440

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

553 / 1308AF: 0.422783

2751 / 6548AF: 0.420128

BipEx

(Bipolar disorder (including schizoaffective))

12336 / 28420AF: 0.434061

12485 / 28844AF: 0.432846

SCHEMA

(Schizophrenia)

29852 / 76468AF: 0.390386

51984 / 136372AF: 0.381193

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.40

(source)

DANN

Benign

0.55

PhyloP100

-4.6

PromoterAI

-0.020

Neutral

(source)

AlphaGenome AVI

Benign

0.29

(source)

GPN-Star LLR

3.5

(source)

GPN-Star score

-0.23

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over