chr19-40277925-T-G

Variant names:

• chr19-40277925-T-G
• rs76137255
• NM_001626.6:c.-85+7256A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001626.6(AKT2):​c.-85+7256A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 152,336 control chromosomes in the GnomAD database, including 85 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 0.025 (85 hom., cov: 32)
• Consequence: AKT2 NM_001626.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.624
• Publications: 4 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=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3797/152336) while in subpopulation NFE AF = 0.0407 (2766/68016). AF 95% confidence interval is 0.0394. There are 85 homozygotes in GnomAd4. There are 1784 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3797 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.-85+7256A>C		intron	N/A	NP_001617.1	P31751-1
	AKT2	NM_001243027.3		c.-234+7256A>C		intron	N/A	NP_001229956.1	B4DG79
	AKT2	NM_001243028.3		c.-141+7256A>C		intron	N/A	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.-85+7256A>C		intron	N/A	ENSP00000375892.2	P31751-1
	AKT2	ENST00000579047.5	TSL:1	c.-141+7256A>C		intron	N/A	ENSP00000471369.1	M0R0P9
	AKT2	ENST00000391844.8	TSL:1	n.-131+7256A>C		intron	N/A	ENSP00000375719.4	J3KT31

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3798 AN: 152218 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0358

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0263

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0249 AC: 3797 AN: 152336 Hom.: 85 Cov.: 32 AF XY: 0.0239 AC XY: 1784 AN XY: 74498

African (AFR) AF: 0.00563 AC: 234 AN: 41594

American (AMR) AF: 0.0148 AC: 227 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 124 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4830

European-Finnish (FIN) AF: 0.0315 AC: 335 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0407 AC: 2766 AN: 68016

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0324 Hom.: 28

Bravo AF: 0.0238

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.70
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism

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: rs76137255; hg19: chr19-40783832;