rs150000674

Variant names:

• chr19-40236272-C-T
• rs150000674
• NM_001626.6:c.945G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001626.6(AKT2):​c.945G>A​(p.Glu315Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: AKT2 NM_001626.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.498
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-40236272-C-T is Benign according to our data. Variant chr19-40236272-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434116.
• BP7: Synonymous conserved (PhyloP=0.498 with no splicing effect.
• BS2: High AC in GnomAd4 at 260 AD gene.

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.945G>A	p.Glu315Glu	synonymous	Exon 10 of 14	NP_001617.1	P31751-1
	AKT2	NM_001243027.3		c.759G>A	p.Glu253Glu	synonymous	Exon 10 of 14	NP_001229956.1	B4DG79
	AKT2	NM_001243028.3		c.759G>A	p.Glu253Glu	synonymous	Exon 9 of 13	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.945G>A	p.Glu315Glu	synonymous	Exon 10 of 14	ENSP00000375892.2	P31751-1
	AKT2	ENST00000579047.5	TSL:1	c.759G>A	p.Glu253Glu	synonymous	Exon 9 of 12	ENSP00000471369.1	M0R0P9
	AKT2	ENST00000311278.10	TSL:1	c.832-168G>A		intron	N/A	ENSP00000309428.6	P31751-2

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00185 AC: 465 AN: 251380 AF XY: 0.00180

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00111 AC: 1629 AN: 1461652 Hom.: 3 Cov.: 36 AF XY: 0.00106 AC XY: 769 AN XY: 727126

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86250

European-Finnish (FIN) AF: 0.0137 AC: 731 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.000734 AC: 816 AN: 1112010

Other (OTH) AF: 0.000994 AC: 60 AN: 60366

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74500

African (AFR) AF: 0.000144 AC: 6 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000745 Hom.: 0

Bravo AF: 0.000461

EpiCase AF: 0.000927

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	AKT2-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Type 2 diabetes mellitus (1)
-	-	1	Type 2 diabetes mellitus;C3278384:Hypoinsulinemic hypoglycemia and body hemihypertrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.4
DANN	Benign	0.49
PhyloP100		0.50
PromoterAI		0.016	Neutral
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150000674; hg19: chr19-40742179; COSMIC: COSV104601671;