19-40236254-C-T

Position:

• chr19-40236254-C-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.960+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,802 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: AKT2 NM_001626.6 splice_region, intron
• Scores: Splicing: ADA: 0.0006715
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.164

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]

AKT2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-40236254-C-T is Benign according to our data. Variant chr19-40236254-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 434115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40236254-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT2	NM_001626.6	c.960+3G>A		splice_region_variant, intron_variant		ENST00000392038.7	NP_001617.1
AKT2	NM_001330511.1	c.832-150G>A		intron_variant			NP_001317440.1
AKT2	NM_001243027.3	c.774+3G>A		splice_region_variant, intron_variant			NP_001229956.1
AKT2	NM_001243028.3	c.774+3G>A		splice_region_variant, intron_variant			NP_001229957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.960+3G>A		splice_region_variant, intron_variant		1	NM_001626.6	ENSP00000375892.2

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00141 AC: 355 AN: 251350 Hom.: 3 AF XY: 0.00152 AC XY: 206 AN XY: 135886

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00104 AC: 1518 AN: 1461482 Hom.: 15 Cov.: 36 AF XY: 0.00112 AC XY: 811 AN XY: 727060

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00341

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.000993 AC XY: 74 AN XY: 74488

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00184

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	AKT2: BP4, BS1 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 23, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

AKT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00067
dbscSNV1_RF	Benign	0.16
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: rs56165898; hg19: chr19-40742161; COSMIC: COSV60910372; COSMIC: COSV60910372;