Genetic Variant AKT2:p.Ser302Gly (chr19-40236313-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001626.6(AKT2):c.904A>G(p.Ser302Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AKT2
NM_001626.6 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.25

Publications

16 publications found

Variant links:

Genes affected

AKT2 (HGNC:392): (AKT serine/threonine kinase 2) This gene is a putative oncogene encoding a protein belonging to a subfamily of serine/threonine kinases containing SH2-like (Src homology 2-like) domains, which is involved in signaling pathways. The gene serves as an oncogene in the tumorigenesis of cancer cells For example, its overexpression contributes to the malignant phenotype of a subset of human ductal pancreatic cancers. The encoded protein is a general protein kinase capable of phophorylating several known proteins, and has also been implicated in insulin signaling. [provided by RefSeq, Nov 2019]

AKT2 Gene-Disease associations (from GenCC):

hypoinsulinemic hypoglycemia and body hemihypertrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
AKT2-related familial partial lipodystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
type 2 diabetes mellitus
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

AKT2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31636354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6 link	c.904A>G	p.Ser302Gly	missense_variant	Exon 10 of 14	ENST00000392038.7	NP_001617.1	P31751-1
AKT2	NM_001243027.3 link	c.718A>G	p.Ser240Gly	missense_variant	Exon 10 of 14		NP_001229956.1	B4DG79
AKT2	NM_001243028.3 link	c.718A>G	p.Ser240Gly	missense_variant	Exon 9 of 13		NP_001229957.1	B4DG79
AKT2	NM_001330511.1 link	c.832-209A>G		intron_variant	Intron 8 of 11		NP_001317440.1	P31751-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7 link	c.904A>G	p.Ser302Gly	missense_variant	Exon 10 of 14	1	NM_001626.6	ENSP00000375892.2		P31751-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neoplasm of the large intestine

Pathogenic:1

Jul 14, 2015

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.0014

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

T;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;.;.

PhyloP100

6.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.0

D;.;.

REVEL

Benign

0.11

Sift

Benign

0.094

T;.;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.19

MutPred

0.27

Gain of ubiquitination at K298 (P = 0.102);.;.;

MVP

0.64

MPC

0.82

ClinPred

0.85

GERP RS

3.7

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.47

Mutation Taster

=40/60

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over