chr19-40246116-C-G

Variant names:

• chr19-40246116-C-G
• rs8100018
• NM_001626.6:c.288-3429G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001626.6(AKT2):​c.288-3429G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 149,930 control chromosomes in the GnomAD database, including 39,883 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (39883 hom., cov: 28)
• Consequence: AKT2 NM_001626.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.57
• Publications: 16 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: 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6	c.288-3429G>C		intron_variant	Intron 4 of 13	ENST00000392038.7	NP_001617.1
AKT2	NM_001330511.1	c.288-3429G>C		intron_variant	Intron 3 of 11		NP_001317440.1
AKT2	NM_001243027.3	c.102-3429G>C		intron_variant	Intron 4 of 13		NP_001229956.1
AKT2	NM_001243028.3	c.102-3429G>C		intron_variant	Intron 3 of 12		NP_001229957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.288-3429G>C		intron_variant	Intron 4 of 13	1	NM_001626.6	ENSP00000375892.2

Frequencies

GnomAD3 genomes AF: 0.727 AC: 109018 AN: 149858 Hom.: 39864 Cov.: 28

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.718

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.728 AC: 109080 AN: 149930 Hom.: 39883 Cov.: 28 AF XY: 0.724 AC XY: 52878 AN XY: 73002

African (AFR) AF: 0.794 AC: 32119 AN: 40458

American (AMR) AF: 0.747 AC: 11267 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2208 AN: 3458

East Asian (EAS) AF: 0.672 AC: 3436 AN: 5114

South Asian (SAS) AF: 0.763 AC: 3658 AN: 4792

European-Finnish (FIN) AF: 0.651 AC: 6464 AN: 9924

Middle Eastern (MID) AF: 0.697 AC: 198 AN: 284

European-Non Finnish (NFE) AF: 0.701 AC: 47567 AN: 67814

Other (OTH) AF: 0.717 AC: 1495 AN: 2084

Alfa AF: 0.611 Hom.: 1577

Bravo AF: 0.736

Asia WGS AF: 0.732 AC: 2548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.20
DANN	Benign	0.31
PhyloP100		-2.6
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: rs8100018; hg19: chr19-40752023;