Genetic Variant NM_001626.6:c.1367A>G (chr19-40233951-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001626.6(AKT2):c.1367A>G(p.Tyr456Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AKT2
NM_001626.6 missense, splice_region

Scores

Splicing: ADA: 0.0006190

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25167668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6 link	c.1367A>G	p.Tyr456Cys	missense_variant, splice_region_variant	Exon 14 of 14	ENST00000392038.7	NP_001617.1	P31751-1
AKT2	NM_001330511.1 link	c.1238A>G	p.Tyr413Cys	missense_variant, splice_region_variant	Exon 12 of 12		NP_001317440.1	P31751-2
AKT2	NM_001243027.3 link	c.1181A>G	p.Tyr394Cys	missense_variant, splice_region_variant	Exon 14 of 14		NP_001229956.1	B4DG79
AKT2	NM_001243028.3 link	c.1181A>G	p.Tyr394Cys	missense_variant, splice_region_variant	Exon 13 of 13		NP_001229957.1	B4DG79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7 link	c.1367A>G	p.Tyr456Cys	missense_variant, splice_region_variant	Exon 14 of 14	1	NM_001626.6	ENSP00000375892.2		P31751-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458358

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725582

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1367A>G (p.Y456C) alteration is located in exon 14 (coding exon 13) of the AKT2 gene. This alteration results from a A to G substitution at nucleotide position 1367, causing the tyrosine (Y) at amino acid position 456 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

T;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.59

T;T;.

M_CAP

Benign

0.023

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.30

N;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.8

N;.;N

REVEL

Benign

0.21

Sift

Benign

0.18

T;.;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0060

B;.;.

Vest4

0.52

MutPred

0.31

Loss of phosphorylation at Y456 (P = 0.0769);.;.;

MVP

0.71

MPC

1.0

ClinPred

0.60

GERP RS

4.2

Varity_R

0.15

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00062

dbscSNV1_RF

Benign

0.0060

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over