rs2304188

Variant names:

• chr19-40236198-T-C
• rs2304188
• NM_001626.6:c.960+59A>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.960+59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,974 control chromosomes in the GnomAD database, including 22,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3860 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18754 hom.)
• Consequence: AKT2 NM_001626.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.122
• Publications: 8 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=-0.8).
• BP6: Variant 19-40236198-T-C is Benign according to our data. Variant chr19-40236198-T-C is described in ClinVar as Benign. ClinVar VariationId is 1238745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT2	NM_001626.6	c.960+59A>G		intron_variant	Intron 10 of 13	ENST00000392038.7	NP_001617.1
AKT2	NM_001330511.1	c.832-94A>G		intron_variant	Intron 8 of 11		NP_001317440.1
AKT2	NM_001243027.3	c.774+59A>G		intron_variant	Intron 10 of 13		NP_001229956.1
AKT2	NM_001243028.3	c.774+59A>G		intron_variant	Intron 9 of 12		NP_001229957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7	c.960+59A>G		intron_variant	Intron 10 of 13	1	NM_001626.6	ENSP00000375892.2

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31345 AN: 151726 Hom.: 3848 Cov.: 32

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.155 AC: 226558 AN: 1461130 Hom.: 18754 Cov.: 35 AF XY: 0.153 AC XY: 111448 AN XY: 726844

African (AFR) AF: 0.341 AC: 11420 AN: 33472

American (AMR) AF: 0.111 AC: 4983 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4469 AN: 26134

East Asian (EAS) AF: 0.143 AC: 5669 AN: 39694

South Asian (SAS) AF: 0.108 AC: 9316 AN: 86230

European-Finnish (FIN) AF: 0.202 AC: 10741 AN: 53208

Middle Eastern (MID) AF: 0.157 AC: 847 AN: 5412

European-Non Finnish (NFE) AF: 0.152 AC: 169055 AN: 1111924

Other (OTH) AF: 0.167 AC: 10058 AN: 60342

GnomAD4 genome AF: 0.207 AC: 31395 AN: 151844 Hom.: 3860 Cov.: 32 AF XY: 0.204 AC XY: 15173 AN XY: 74224

African (AFR) AF: 0.337 AC: 13948 AN: 41400

American (AMR) AF: 0.158 AC: 2412 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3466

East Asian (EAS) AF: 0.136 AC: 700 AN: 5148

South Asian (SAS) AF: 0.107 AC: 514 AN: 4820

European-Finnish (FIN) AF: 0.195 AC: 2064 AN: 10570

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10481 AN: 67854

Other (OTH) AF: 0.192 AC: 406 AN: 2110

Alfa AF: 0.175 Hom.: 1163

Bravo AF: 0.209

Asia WGS AF: 0.135 AC: 470 AN: 3478

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.1
DANN	Benign	0.76
PhyloP100		-0.12
PromoterAI		0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2304188; hg19: chr19-40742105; COSMIC: COSV107324315; COSMIC: COSV107324315;