19-40233951-T-C

Variant names:

• chr19-40233951-T-C
• NM_001626.6:c.1367A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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

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 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	c.1367A>G	p.Tyr456Cys	missense_variant, splice_region_variant	Exon 14 of 14	ENST00000392038.7	NP_001617.1
AKT2	NM_001330511.1	c.1238A>G	p.Tyr413Cys	missense_variant, splice_region_variant	Exon 12 of 12		NP_001317440.1
AKT2	NM_001243027.3	c.1181A>G	p.Tyr394Cys	missense_variant, splice_region_variant	Exon 14 of 14		NP_001229956.1
AKT2	NM_001243028.3	c.1181A>G	p.Tyr394Cys	missense_variant, splice_region_variant	Exon 13 of 13		NP_001229957.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458358 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725582

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.59	T;T;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.30	N;.;.
PrimateAI	Uncertain	0.74	T
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	D
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.

Other links and lift over

hg19: chr19-40739858;