19-40235026-G-T

Variant names:

• chr19-40235026-G-T
• rs148795214
• ENST00000579047.5:c.1199C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000579047.5(AKT2):​c.1199C>A​(p.Pro400Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P400L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AKT2 ENST00000579047.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.835
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.120978564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000579047.5. 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
	AKT2	NM_001626.6	MANE Select	c.1366+19C>A		intron	N/A	NP_001617.1	P31751-1
	AKT2	NM_001330511.1		c.1237+19C>A		intron	N/A	NP_001317440.1	P31751-2
	AKT2	NM_001243027.3		c.1180+19C>A		intron	N/A	NP_001229956.1	B4DG79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT2	ENST00000579047.5	TSL:1	c.1199C>A	p.Pro400Gln	missense	Exon 12 of 12	ENSP00000471369.1	M0R0P9
	AKT2	ENST00000392038.7	TSL:1 MANE Select	c.1366+19C>A		intron	N/A	ENSP00000375892.2	P31751-1
	AKT2	ENST00000311278.10	TSL:1	c.1237+19C>A		intron	N/A	ENSP00000309428.6	P31751-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456314 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724872

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106966

Other (OTH) AF: 0.00 AC: 0 AN: 60204

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.037
DANN	Benign	0.79
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.12	T
PhyloP100		-0.83
Sift4G	Uncertain	0.043	D
Vest4		0.20
MVP		0.80
GERP RS		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148795214; hg19: chr19-40740933;