rs33933140

Variant names:

• chr19-40233606-A-G
• rs33933140
• NM_001626.6:c.*266T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001626.6(AKT2):​c.*266T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 726,250 control chromosomes in the GnomAD database, including 82,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13469 hom., cov: 31)
  • Exomes 𝑓: 0.48 (69227 hom.)
• Consequence: AKT2 NM_001626.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.649
• Publications: 24 publications found

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.024).
• BP6: Variant 19-40233606-A-G is Benign according to our data. Variant chr19-40233606-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001626.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT2	NM_001626.6	MANE Select	c.*266T>C		3_prime_UTR	Exon 14 of 14	NP_001617.1	P31751-1
	AKT2	NM_001330511.1		c.*266T>C		3_prime_UTR	Exon 12 of 12	NP_001317440.1	P31751-2
	AKT2	NM_001243027.3		c.*266T>C		3_prime_UTR	Exon 14 of 14	NP_001229956.1	B4DG79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT2	ENST00000392038.7	TSL:1 MANE Select	c.*266T>C		3_prime_UTR	Exon 14 of 14	ENSP00000375892.2	P31751-1
	AKT2	ENST00000870029.1		c.*266T>C		3_prime_UTR	Exon 15 of 15	ENSP00000540088.1
	AKT2	ENST00000870030.1		c.*266T>C		3_prime_UTR	Exon 15 of 15	ENSP00000540089.1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60365 AN: 151702 Hom.: 13469 Cov.: 31

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.490 AC: 113125 AN: 231026 AF XY: 0.492

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.603

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.527

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.474

Gnomad OTH exome AF: 0.482

GnomAD4 exome AF: 0.482 AC: 277079 AN: 574430 Hom.: 69227 Cov.: 2 AF XY: 0.487 AC XY: 153293 AN XY: 314560

African (AFR) AF: 0.177 AC: 3021 AN: 17078

American (AMR) AF: 0.598 AC: 25255 AN: 42250

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 7582 AN: 20040

East Asian (EAS) AF: 0.473 AC: 15806 AN: 33422

South Asian (SAS) AF: 0.591 AC: 40568 AN: 68598

European-Finnish (FIN) AF: 0.446 AC: 15023 AN: 33678

Middle Eastern (MID) AF: 0.412 AC: 1633 AN: 3968

European-Non Finnish (NFE) AF: 0.474 AC: 153841 AN: 324634

Other (OTH) AF: 0.466 AC: 14350 AN: 30762

GnomAD4 genome AF: 0.398 AC: 60374 AN: 151820 Hom.: 13469 Cov.: 31 AF XY: 0.400 AC XY: 29640 AN XY: 74172

African (AFR) AF: 0.185 AC: 7646 AN: 41420

American (AMR) AF: 0.510 AC: 7786 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2584 AN: 5118

South Asian (SAS) AF: 0.595 AC: 2858 AN: 4804

European-Finnish (FIN) AF: 0.433 AC: 4564 AN: 10538

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32261 AN: 67886

Other (OTH) AF: 0.410 AC: 865 AN: 2112

Alfa AF: 0.446 Hom.: 9591

Bravo AF: 0.393

Asia WGS AF: 0.535 AC: 1859 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.0
DANN	Benign	0.62
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs33933140; hg19: chr19-40739513; COSMIC: COSV60908566; COSMIC: COSV60908566;