19-40234939-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000579047.5(AKT2):c.1286A>G(p.His429Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 in 1,034,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: AKT2 ENST00000579047.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01946044).
• BP6: Variant 19-40234939-T-C is Benign according to our data. Variant chr19-40234939-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3067186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT2	NM_001626.6	c.1366+106A>G		intron_variant		ENST00000392038.7
AKT2	NM_001243027.3	c.1180+106A>G		intron_variant
AKT2	NM_001243028.3	c.1180+106A>G		intron_variant
AKT2	NM_001330511.1	c.1237+106A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT2	ENST00000392038.7	c.1366+106A>G		intron_variant		1	NM_001626.6	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000431 AC: 75 AN: 174188 Hom.: 0 AF XY: 0.000427 AC XY: 40 AN XY: 93758

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000801

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000839

Gnomad OTH exome AF: 0.000417

GnomAD4 exome AF: 0.000586 AC: 517 AN: 882672 Hom.: 0 Cov.: 12 AF XY: 0.000569 AC XY: 260 AN XY: 456778

Gnomad4 AFR exome AF: 0.0000450

Gnomad4 AMR exome AF: 0.000306

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000424

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000779

Gnomad4 OTH exome AF: 0.000771

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74366

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000239 AC: 28

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

AKT2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	0.053
Dann	Benign	0.52
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.019	T
MutationTaster	Benign	1.0	N;N;N
Sift4G	Pathogenic	0.0	D
Vest4		0.085
MVP		0.79
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs187555784; hg19: chr19-40740846;