rs3730051

Variant names:

• chr19-40238790-T-C
• rs3730051
• NM_001626.6:c.708+115A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001626.6(AKT2):​c.708+115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,118,092 control chromosomes in the GnomAD database, including 37,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4718 hom., cov: 31)
  • Exomes 𝑓: 0.26 (32895 hom.)
• Consequence: AKT2 NM_001626.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.78
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-40238790-T-C is Benign according to our data. Variant chr19-40238790-T-C is described in ClinVar as Benign. ClinVar VariationId is 1233959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6	c.708+115A>G		intron_variant	Intron 8 of 13	ENST00000392038.7	NP_001617.1
AKT2	NM_001330511.1	c.708+115A>G		intron_variant	Intron 7 of 11		NP_001317440.1
AKT2	NM_001243027.3	c.522+115A>G		intron_variant	Intron 8 of 13		NP_001229956.1
AKT2	NM_001243028.3	c.522+115A>G		intron_variant	Intron 7 of 12		NP_001229957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.708+115A>G		intron_variant	Intron 8 of 13	1	NM_001626.6	ENSP00000375892.2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37228 AN: 151764 Hom.: 4722 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.257 AC: 247838 AN: 966210 Hom.: 32895 AF XY: 0.255 AC XY: 127557 AN XY: 500892

African (AFR) AF: 0.188 AC: 4481 AN: 23874

American (AMR) AF: 0.228 AC: 9859 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 8252 AN: 22914

East Asian (EAS) AF: 0.317 AC: 11806 AN: 37202

South Asian (SAS) AF: 0.173 AC: 13139 AN: 76052

European-Finnish (FIN) AF: 0.312 AC: 14906 AN: 47850

Middle Eastern (MID) AF: 0.267 AC: 1275 AN: 4776

European-Non Finnish (NFE) AF: 0.260 AC: 172949 AN: 666062

Other (OTH) AF: 0.253 AC: 11171 AN: 44202

GnomAD4 genome AF: 0.245 AC: 37245 AN: 151882 Hom.: 4718 Cov.: 31 AF XY: 0.249 AC XY: 18496 AN XY: 74216

African (AFR) AF: 0.190 AC: 7877 AN: 41410

American (AMR) AF: 0.241 AC: 3675 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1202 AN: 3470

East Asian (EAS) AF: 0.284 AC: 1464 AN: 5162

South Asian (SAS) AF: 0.172 AC: 827 AN: 4804

European-Finnish (FIN) AF: 0.331 AC: 3493 AN: 10544

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17833 AN: 67926

Other (OTH) AF: 0.260 AC: 546 AN: 2104

Alfa AF: 0.252 Hom.: 771

Bravo AF: 0.238

Asia WGS AF: 0.214 AC: 742 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.61
PhyloP100		-1.8
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: rs3730051; hg19: chr19-40744697; COSMIC: COSV60910946; COSMIC: COSV60910946;