rs3730050

Variant names:

• chr19-40265075-T-C
• rs3730050
• NM_001626.6:c.46+147A>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.46+147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,193,186 control chromosomes in the GnomAD database, including 302,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40491 hom., cov: 32)
  • Exomes 𝑓: 0.71 (262233 hom.)
• Consequence: AKT2 NM_001626.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.11
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-40265075-T-C is Benign according to our data. Variant chr19-40265075-T-C is described in ClinVar as Benign. ClinVar VariationId is 1182081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.788 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.46+147A>G		intron	N/A	NP_001617.1	P31751-1
	AKT2	NM_001330511.1		c.46+147A>G		intron	N/A	NP_001317440.1	P31751-2
	AKT2	NM_001243027.3		c.-141+184A>G		intron	N/A	NP_001229956.1	B4DG79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT2	ENST00000392038.7	TSL:1 MANE Select	c.46+147A>G		intron	N/A	ENSP00000375892.2	P31751-1
	AKT2	ENST00000579047.5	TSL:1	c.-140-8021A>G		intron	N/A	ENSP00000471369.1	M0R0P9
	AKT2	ENST00000311278.10	TSL:1	c.46+147A>G		intron	N/A	ENSP00000309428.6	P31751-2

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110616 AN: 152000 Hom.: 40459 Cov.: 32

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.708 AC: 737269 AN: 1041068 Hom.: 262233 AF XY: 0.709 AC XY: 372646 AN XY: 525516

African (AFR) AF: 0.798 AC: 19683 AN: 24676

American (AMR) AF: 0.759 AC: 26142 AN: 34420

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 13972 AN: 22398

East Asian (EAS) AF: 0.649 AC: 22016 AN: 33932

South Asian (SAS) AF: 0.765 AC: 54280 AN: 70974

European-Finnish (FIN) AF: 0.669 AC: 25654 AN: 38352

Middle Eastern (MID) AF: 0.712 AC: 2437 AN: 3422

European-Non Finnish (NFE) AF: 0.704 AC: 540032 AN: 766708

Other (OTH) AF: 0.716 AC: 33053 AN: 46186

GnomAD4 genome AF: 0.728 AC: 110712 AN: 152118 Hom.: 40491 Cov.: 32 AF XY: 0.725 AC XY: 53884 AN XY: 74352

African (AFR) AF: 0.795 AC: 32984 AN: 41502

American (AMR) AF: 0.745 AC: 11398 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 2209 AN: 3470

East Asian (EAS) AF: 0.673 AC: 3472 AN: 5162

South Asian (SAS) AF: 0.768 AC: 3709 AN: 4830

European-Finnish (FIN) AF: 0.654 AC: 6913 AN: 10572

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47645 AN: 67972

Other (OTH) AF: 0.716 AC: 1513 AN: 2114

Alfa AF: 0.709 Hom.: 19595

Bravo AF: 0.735

Asia WGS AF: 0.736 AC: 2561 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0090
DANN	Benign	0.21
PhyloP100		-3.1
PromoterAI		-0.0082	Neutral
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: rs3730050; hg19: chr19-40770982;