19-40236254-C-T

Position:

chr19-40236254-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001626.6(AKT2):c.960+3G>A variant causes a splice donor 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. 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_donor_region, intron

Scores

Splicing: ADA: 0.0006715

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.164

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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	Effect	MANE	Protein
AKT2	NM_001626.6 linkuse as main transcript	c.960+3G>A	splice_donor_region_variant, intron_variant	ENST00000392038.7	NP_001617.1
AKT2	NM_001243027.3 linkuse as main transcript	c.774+3G>A	splice_donor_region_variant, intron_variant		NP_001229956.1
AKT2	NM_001243028.3 linkuse as main transcript	c.774+3G>A	splice_donor_region_variant, intron_variant		NP_001229957.1
AKT2	NM_001330511.1 linkuse as main transcript	c.832-150G>A	intron_variant		NP_001317440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7 linkuse as main transcript	c.960+3G>A		splice_donor_region_variant, intron_variant		1	NM_001626.6	ENSP00000375892	P1	P31751-1

Frequencies

GnomAD3 genomes

AF:

0.000959

AC:

146

AN:

152202

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00152

AC XY:

206

AN XY:

135886

show subpopulations

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.:

Cov.:

AF XY:

0.00112

AC XY:

811

AN XY:

727060

show subpopulations

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.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

74488

show subpopulations

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.:

Bravo

AF:

0.00110

Asia WGS

AF:

0.00144

AC:

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

LINK: link

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	Apr 01, 2023	AKT2: BP4 -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over