rs121434593
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate
The NM_001626.6(AKT2):c.821G>A(p.Arg274His) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R274R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
AKT2
NM_001626.6 missense
NM_001626.6 missense
Scores
11
6
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, AKT2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
?
Variant 19-40237979-C-T is Pathogenic according to our data. Variant chr19-40237979-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13982.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AKT2 | NM_001626.6 | c.821G>A | p.Arg274His | missense_variant | 9/14 | ENST00000392038.7 | |
AKT2 | NM_001330511.1 | c.821G>A | p.Arg274His | missense_variant | 8/12 | ||
AKT2 | NM_001243027.3 | c.635G>A | p.Arg212His | missense_variant | 9/14 | ||
AKT2 | NM_001243028.3 | c.635G>A | p.Arg212His | missense_variant | 8/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AKT2 | ENST00000392038.7 | c.821G>A | p.Arg274His | missense_variant | 9/14 | 1 | NM_001626.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2009 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2023 | Observed in a family with severe insulin resistance and diabetes mellitus (George et al., 2004); Published functional studies demonstrate a damaging effect to protein function in human liver cells and rat fat cells (George et al., 2004; Chan et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22031698, 19164855, 33901270, 35755045, 35250856, 37105912, 33893069, 15166380) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;.;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;.;.
Sift4G
Uncertain
D;D;D;D;.
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of methylation at K277 (P = 0.1057);Gain of methylation at K277 (P = 0.1057);Gain of methylation at K277 (P = 0.1057);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at