rs10416620

Variant names:

• chr19-40285576-C-G
• rs10416620
• NM_001626.6:c.-480G>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.-480G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 372,500 control chromosomes in the GnomAD database, including 7,642 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 0.22 (4368 hom., cov: 31)
  • Exomes 𝑓: 0.17 (3274 hom.)
• Consequence: AKT2 NM_001626.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 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.-480G>C		upstream_gene	N/A	NP_001617.1	P31751-1
	AKT2	NM_001243027.3		c.-629G>C		upstream_gene	N/A	NP_001229956.1	B4DG79
	AKT2	NM_001243028.3		c.-536G>C		upstream_gene	N/A	NP_001229957.1	B4DG79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT2	ENST00000392038.7	TSL:1 MANE Select	c.-480G>C		upstream_gene	N/A	ENSP00000375892.2	P31751-1
	AKT2	ENST00000579047.5	TSL:1	c.-536G>C		upstream_gene	N/A	ENSP00000471369.1	M0R0P9
	AKT2	ENST00000391844.8	TSL:1	n.-526G>C		upstream_gene	N/A	ENSP00000375719.4	J3KT31

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32925 AN: 152004 Hom.: 4351 Cov.: 31

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.166 AC: 36608 AN: 220378 Hom.: 3274 Cov.: 0 AF XY: 0.165 AC XY: 18502 AN XY: 112178

African (AFR) AF: 0.368 AC: 2319 AN: 6300

American (AMR) AF: 0.127 AC: 828 AN: 6512

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 1345 AN: 8162

East Asian (EAS) AF: 0.153 AC: 3144 AN: 20550

South Asian (SAS) AF: 0.104 AC: 209 AN: 2000

European-Finnish (FIN) AF: 0.201 AC: 3933 AN: 19570

Middle Eastern (MID) AF: 0.150 AC: 171 AN: 1140

European-Non Finnish (NFE) AF: 0.156 AC: 22061 AN: 141664

Other (OTH) AF: 0.179 AC: 2598 AN: 14480

GnomAD4 genome AF: 0.217 AC: 32982 AN: 152122 Hom.: 4368 Cov.: 31 AF XY: 0.215 AC XY: 15961 AN XY: 74374

African (AFR) AF: 0.367 AC: 15235 AN: 41476

American (AMR) AF: 0.160 AC: 2453 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3472

East Asian (EAS) AF: 0.137 AC: 711 AN: 5174

South Asian (SAS) AF: 0.105 AC: 508 AN: 4826

European-Finnish (FIN) AF: 0.195 AC: 2068 AN: 10590

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10729 AN: 67972

Other (OTH) AF: 0.199 AC: 420 AN: 2112

Alfa AF: 0.200 Hom.: 442

Bravo AF: 0.221

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.2
DANN	Benign	0.47
PhyloP100		0.12
PromoterAI		-0.048	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10416620; hg19: chr19-40791483;