19-40257052-C-T

Position:

• chr19-40257052-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT2 NM_001626.6 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• 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]

AKT2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AKT2. . Gene score misZ 2.4133 (greater than the threshold 3.09). Trascript score misZ 3.4177 (greater than threshold 3.09). GenCC has associacion of gene with AKT2-related familial partial lipodystrophy, type 2 diabetes mellitus, diabetes mellitus, noninsulin-dependent, hypoinsulinemic hypoglycemia and body hemihypertrophy.
• 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 no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	3/14	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:2

Revision: no assertion criteria provided

Submissions by phenotype

Hypoinsulinemic hypoglycemia and body hemihypertrophy Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jun 07, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 28, 2011	- -

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;