ENST00000391844.8:n.*1118C>A

Variant names:

• chr19-40233814-G-T
• rs2304186
• ENST00000391844.8:n.*1118C>A

Variant summary

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

The ENST00000391844.8(AKT2):​n.*1118C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,573,762 control chromosomes in the GnomAD database, including 180,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13281 hom., cov: 31)
  • Exomes 𝑓: 0.48 (166916 hom.)
• Consequence: AKT2 ENST00000391844.8 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.362
• Publications: 32 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=-0.85).
• BP6: Variant 19-40233814-G-T is Benign according to our data. Variant chr19-40233814-G-T is described in ClinVar as Benign. ClinVar VariationId is 1224269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6	c.*58C>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000392038.7	NP_001617.1
AKT2	NM_001330511.1	c.*58C>A		3_prime_UTR_variant	Exon 12 of 12		NP_001317440.1
AKT2	NM_001243027.3	c.*58C>A		3_prime_UTR_variant	Exon 14 of 14		NP_001229956.1
AKT2	NM_001243028.3	c.*58C>A		3_prime_UTR_variant	Exon 13 of 13		NP_001229957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.*58C>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_001626.6	ENSP00000375892.2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59904 AN: 151718 Hom.: 13281 Cov.: 31

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.401

GnomAD4 exome AF: 0.480 AC: 682051 AN: 1421932 Hom.: 166916 Cov.: 28 AF XY: 0.482 AC XY: 341182 AN XY: 707504

African (AFR) AF: 0.162 AC: 5341 AN: 32904

American (AMR) AF: 0.595 AC: 26351 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 9730 AN: 25782

East Asian (EAS) AF: 0.460 AC: 18078 AN: 39326

South Asian (SAS) AF: 0.589 AC: 50326 AN: 85466

European-Finnish (FIN) AF: 0.445 AC: 18356 AN: 41288

Middle Eastern (MID) AF: 0.409 AC: 2325 AN: 5684

European-Non Finnish (NFE) AF: 0.482 AC: 523938 AN: 1088030

Other (OTH) AF: 0.466 AC: 27606 AN: 59194

GnomAD4 genome AF: 0.395 AC: 59910 AN: 151830 Hom.: 13281 Cov.: 31 AF XY: 0.396 AC XY: 29408 AN XY: 74180

African (AFR) AF: 0.180 AC: 7475 AN: 41420

American (AMR) AF: 0.508 AC: 7758 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1348 AN: 3468

East Asian (EAS) AF: 0.483 AC: 2478 AN: 5134

South Asian (SAS) AF: 0.590 AC: 2839 AN: 4812

European-Finnish (FIN) AF: 0.430 AC: 4528 AN: 10524

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.474 AC: 32180 AN: 67898

Other (OTH) AF: 0.402 AC: 848 AN: 2110

Alfa AF: 0.451 Hom.: 18015

Bravo AF: 0.391

Asia WGS AF: 0.518 AC: 1802 AN: 3476

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

This variant is associated with the following publications: (PMID: 33768461) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.48
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2304186; hg19: chr19-40739721; COSMIC: COSV60908207; COSMIC: COSV60908207;