19-40257052-C-T

Variant names:

• chr19-40257052-C-T
• rs387906659
• NM_001626.6:c.49G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001626.6(AKT2):​c.49G>A​(p.Glu17Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT2 NM_001626.6 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• PP5: Variant 19-40257052-C-T is Pathogenic according to our data. Variant chr19-40257052-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29804.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000392038.7	NP_001617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_001626.6	ENSP00000375892.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hypoinsulinemic hypoglycemia and body hemihypertrophy Pathogenic:2

Jun 07, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Type 2 diabetes mellitus;C3278384:Hypoinsulinemic hypoglycemia and body hemihypertrophy Pathogenic:1

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 17 of the AKT2 protein (p.Glu17Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypoinsulinemic hypoglycemia with hemihypertrophy (PMID: 21979934). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29804). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects AKT2 function (PMID: 21979934). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.;.;.;D;.;D;.;.;D;.;.;D;D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;D;D;D;.;.;D;D;D;.;D;.;D;.;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;D;D;.;.;D;D;D;.;D;.;D;.;.;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D;.;D;.;.;.;.;.;.;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.62		Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);Gain of MoRF binding (P = 0.0194);
MVP		0.73
MPC		1.1
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.65
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906659; hg19: chr19-40762959; COSMIC: COSV60907479; COSMIC: COSV60907479;