chr19-40235048-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001626.6(AKT2):c.1363C>T(p.Arg455Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
AKT2
NM_001626.6 missense
NM_001626.6 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 0.771
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_benign. Variant got -4 ACMG points.
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.30778185).
BS2
High AC in GnomAdExome4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AKT2 | NM_001626.6 | c.1363C>T | p.Arg455Cys | missense_variant | 13/14 | ENST00000392038.7 | NP_001617.1 | |
AKT2 | NM_001330511.1 | c.1234C>T | p.Arg412Cys | missense_variant | 11/12 | NP_001317440.1 | ||
AKT2 | NM_001243027.3 | c.1177C>T | p.Arg393Cys | missense_variant | 13/14 | NP_001229956.1 | ||
AKT2 | NM_001243028.3 | c.1177C>T | p.Arg393Cys | missense_variant | 12/13 | NP_001229957.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AKT2 | ENST00000392038.7 | c.1363C>T | p.Arg455Cys | missense_variant | 13/14 | 1 | NM_001626.6 | ENSP00000375892 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251104Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135840
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727148
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Type 2 diabetes mellitus;C3278384:Hypoinsulinemic hypoglycemia and body hemihypertrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 13, 2023 | 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 853867). This variant has not been reported in the literature in individuals affected with AKT2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 455 of the AKT2 protein (p.Arg455Cys). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;.
REVEL
Benign
Sift
Uncertain
D;.;D;.
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at