chr19-40285605-G-A

Variant names:

• chr19-40285605-G-A
• rs7254617
• ENST00000391844.8:n.-555C>T

Variant summary

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

The ENST00000578123.5(AKT2):​c.-242C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 357,842 control chromosomes in the GnomAD database, including 7,394 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 (4355 hom., cov: 31)
  • Exomes 𝑓: 0.17 (3039 hom.)
• Consequence: AKT2 ENST00000578123.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.944
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Orphanet
• 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: ENST00000578123.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT2	ENST00000391844.8	TSL:1	n.-555C>T		upstream_gene	N/A	ENSP00000375719.4	J3KT31
	AKT2	ENST00000424901.5	TSL:5	c.-509C>T		upstream_gene	N/A	ENSP00000399532.2	P31751-2
	AKT2	ENST00000578123.5	TSL:4	c.-242C>T		upstream_gene	N/A	ENSP00000462022.1	J3KRI8

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32900 AN: 151924 Hom.: 4338 Cov.: 31

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.167 AC: 34289 AN: 205800 Hom.: 3039 AF XY: 0.166 AC XY: 17355 AN XY: 104824

African (AFR) AF: 0.366 AC: 2175 AN: 5936

American (AMR) AF: 0.127 AC: 763 AN: 6008

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 1295 AN: 7614

East Asian (EAS) AF: 0.153 AC: 2943 AN: 19232

South Asian (SAS) AF: 0.109 AC: 203 AN: 1862

European-Finnish (FIN) AF: 0.202 AC: 3686 AN: 18272

Middle Eastern (MID) AF: 0.147 AC: 158 AN: 1072

European-Non Finnish (NFE) AF: 0.156 AC: 20635 AN: 132314

Other (OTH) AF: 0.180 AC: 2431 AN: 13490

GnomAD4 genome AF: 0.217 AC: 32957 AN: 152042 Hom.: 4355 Cov.: 31 AF XY: 0.214 AC XY: 15936 AN XY: 74320

African (AFR) AF: 0.367 AC: 15219 AN: 41460

American (AMR) AF: 0.161 AC: 2455 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 587 AN: 3470

East Asian (EAS) AF: 0.137 AC: 709 AN: 5162

South Asian (SAS) AF: 0.105 AC: 506 AN: 4818

European-Finnish (FIN) AF: 0.195 AC: 2064 AN: 10572

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10711 AN: 67950

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

Alfa AF: 0.119 Hom.: 259

Bravo AF: 0.221

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.50
DANN	Benign	0.80
PhyloP100		-0.94
PromoterAI		0.037	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7254617; hg19: chr19-40791512;