rs201884933

chr19-40242077-G-Achr19-40242077-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001626.6(AKT2):c.442-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,614,070 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (3 hom.)
• Consequence: AKT2 NM_001626.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001908
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00100

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-40242077-G-A is Benign according to our data. Variant chr19-40242077-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT2	NM_001626.6	c.442-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000392038.7
AKT2	NM_001243027.3	c.256-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
AKT2	NM_001243028.3	c.256-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
AKT2	NM_001330511.1	c.442-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT2	ENST00000392038.7	c.442-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001626.6	P1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000446 AC: 112 AN: 251316 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135882

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000786 AC: 1149 AN: 1461816 Hom.: 3 Cov.: 31 AF XY: 0.000787 AC XY: 572 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000952

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000539 AC: 82 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74384

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000976 Hom.: 0

Bravo AF: 0.000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 18, 2016

- -

Type 2 diabetes mellitus;C3278384:Hypoinsulinemic hypoglycemia and body hemihypertrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

AKT2: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	12
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0020
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: rs201884933; hg19: chr19-40747984; COSMIC: COSV105881116; COSMIC: COSV105881116;