rs35588791

Variant names:

• chr19-40257008-G-A
• rs35588791
• NM_001626.6:c.93C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001626.6(AKT2):​c.93C>T​(p.Ser31Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,614,128 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (37 hom.)
• Consequence: AKT2 NM_001626.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00500
• Publications: 9 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-40257008-G-A is Benign according to our data. Variant chr19-40257008-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.
• BS2: High AC in GnomAd4 at 446 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.93C>T	p.Ser31Ser	synonymous	Exon 3 of 14	NP_001617.1	P31751-1
	AKT2	NM_001330511.1		c.93C>T	p.Ser31Ser	synonymous	Exon 2 of 12	NP_001317440.1	P31751-2
	AKT2	NM_001243027.3		c.-94C>T		5_prime_UTR	Exon 3 of 14	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.93C>T	p.Ser31Ser	synonymous	Exon 3 of 14	ENSP00000375892.2	P31751-1
	AKT2	ENST00000311278.10	TSL:1	c.93C>T	p.Ser31Ser	synonymous	Exon 2 of 12	ENSP00000309428.6	P31751-2
	AKT2	ENST00000579047.5	TSL:1	c.-94C>T		5_prime_UTR	Exon 2 of 12	ENSP00000471369.1	M0R0P9

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00357 AC: 898 AN: 251480 AF XY: 0.00413

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00439 AC: 6413 AN: 1461808 Hom.: 37 Cov.: 32 AF XY: 0.00457 AC XY: 3324 AN XY: 727212

African (AFR) AF: 0.000388 AC: 13 AN: 33476

American (AMR) AF: 0.00110 AC: 49 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0113 AC: 975 AN: 86254

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53414

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.00453 AC: 5032 AN: 1111944

Other (OTH) AF: 0.00384 AC: 232 AN: 60394

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74478

African (AFR) AF: 0.000601 AC: 25 AN: 41568

American (AMR) AF: 0.00333 AC: 51 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00444 AC: 302 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00354 Hom.: 2

Bravo AF: 0.00292

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Type 2 diabetes mellitus (1)
-	-	1	Type 2 diabetes mellitus;C3278384:Hypoinsulinemic hypoglycemia and body hemihypertrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		0.0050
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=297/3	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: rs35588791; hg19: chr19-40762915; COSMIC: COSV104601572;