19-40233863-G-A

Variant names:

• chr19-40233863-G-A
• rs79275829
• NM_001626.6:c.*9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001626.6(AKT2):​c.*9C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 1,610,172 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (107 hom.)
• Consequence: AKT2 NM_001626.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0460
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-40233863-G-A is Benign according to our data. Variant chr19-40233863-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1338691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0088 (1340/152352) while in subpopulation AMR AF = 0.0178 (273/15310). AF 95% confidence interval is 0.0161. There are 8 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1340 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.*9C>T		3_prime_UTR	Exon 14 of 14	NP_001617.1	P31751-1
	AKT2	NM_001330511.1		c.*9C>T		3_prime_UTR	Exon 12 of 12	NP_001317440.1	P31751-2
	AKT2	NM_001243027.3		c.*9C>T		3_prime_UTR	Exon 14 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.*9C>T		3_prime_UTR	Exon 14 of 14	ENSP00000375892.2	P31751-1
	AKT2	ENST00000311278.10	TSL:1	c.*9C>T		3_prime_UTR	Exon 12 of 12	ENSP00000309428.6	P31751-2
	AKT2	ENST00000391844.8	TSL:1	n.*1069C>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000375719.4	J3KT31

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1341 AN: 152234 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00864 AC: 2120 AN: 245300 AF XY: 0.00921

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00953

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00980 AC: 14287 AN: 1457820 Hom.: 107 Cov.: 32 AF XY: 0.00989 AC XY: 7176 AN XY: 725386

African (AFR) AF: 0.00167 AC: 56 AN: 33476

American (AMR) AF: 0.0107 AC: 479 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 323 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00525 AC: 453 AN: 86232

European-Finnish (FIN) AF: 0.00203 AC: 101 AN: 49802

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5760

European-Non Finnish (NFE) AF: 0.0109 AC: 12088 AN: 1111698

Other (OTH) AF: 0.0105 AC: 632 AN: 60344

GnomAD4 genome AF: 0.00880 AC: 1340 AN: 152352 Hom.: 8 Cov.: 32 AF XY: 0.00846 AC XY: 630 AN XY: 74496

African (AFR) AF: 0.00274 AC: 114 AN: 41580

American (AMR) AF: 0.0178 AC: 273 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10626

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 834 AN: 68032

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0107 Hom.: 6

Bravo AF: 0.0101

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.77
PhyloP100		-0.046
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs79275829; hg19: chr19-40739770; COSMIC: COSV60907968;