19-40236254-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hypoinsulinemic hypoglycemia and body hemihypertrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
AKT2-related familial partial lipodystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
type 2 diabetes mellitus
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

AKT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 434115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6 link	c.960+3G>A	splice_region_variant, intron_variant	Intron 10 of 13	ENST00000392038.7	NP_001617.1	P31751-1
AKT2	NM_001330511.1 link	c.832-150G>A	intron_variant	Intron 8 of 11		NP_001317440.1	P31751-2
AKT2	NM_001243027.3 link	c.774+3G>A	splice_region_variant, intron_variant	Intron 10 of 13		NP_001229956.1	B4DG79
AKT2	NM_001243028.3 link	c.774+3G>A	splice_region_variant, intron_variant	Intron 9 of 12		NP_001229957.1	B4DG79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7 link	c.960+3G>A		splice_region_variant, intron_variant	Intron 10 of 13	1	NM_001626.6	ENSP00000375892.2		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

GnomAD2 exomes

AF:

0.00141

AC:

355

AN:

251350

AF XY:

0.00152

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 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

African (AFR)

AF:

0.000657

AC:

AN:

33474

American (AMR)

AF:

0.000604

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

308

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00341

AC:

294

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.0178

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.000575

AC:

639

AN:

1112006

Other (OTH)

AF:

0.00215

AC:

130

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

204

306

408

510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000959

AC:

146

AN:

152320

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41582

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000971

AC:

AN:

68006

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AKT2: BP4, BS1 -

not specified

Benign:1

Feb 23, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AKT2-related disorder

Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Benign

0.55

PhyloP100

0.16

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=26/74

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over