rs35588791

Positions:

• chr19-40257008-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001626.6(AKT2):​c.93C>T​(p.Ser31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,614,128 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (37 hom.)
• Consequence: AKT2 NM_001626.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00500

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-40257008-G-A is Benign according to our data. Variant chr19-40257008-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40257008-G-A is described in Lovd as [Likely_benign]. Variant chr19-40257008-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.
• BS2: High AC in GnomAd4 at 446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT2	NM_001626.6	c.93C>T	p.Ser31=	synonymous_variant	3/14	ENST00000392038.7
AKT2	NM_001330511.1	c.93C>T	p.Ser31=	synonymous_variant	2/12
AKT2	NM_001243027.3	c.-94C>T		5_prime_UTR_variant	3/14
AKT2	NM_001243028.3	c.-94C>T		5_prime_UTR_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT2	ENST00000392038.7	c.93C>T	p.Ser31=	synonymous_variant	3/14	1	NM_001626.6	P1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00357 AC: 898 AN: 251480 Hom.: 3 AF XY: 0.00413 AC XY: 562 AN XY: 135914

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00439 AC: 6413 AN: 1461808 Hom.: 37 Cov.: 32 AF XY: 0.00457 AC XY: 3324 AN XY: 727212

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00453

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74478

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00444

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00292

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2019	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	AKT2: BP4, BP7, BS1, BS2 -

Type 2 diabetes mellitus Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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Potent mutationsin AKT2 gene are associated with familial partial lipodystrophy and in terms of metabolic abnormality, can present with insulin resistance, hyperglycemia and Diabetes. In, silico analysis revealed that this particular rs35588791 is prevalent with Type 2 Diabetes -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35588791; hg19: chr19-40762915; COSMIC: COSV104601572; COSMIC: COSV104601572;