19-40235367-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001626.6(AKT2):c.1176-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,612,978 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (26 hom.)
• Consequence: AKT2 NM_001626.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0280

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-40235367-G-A is Benign according to our data. Variant chr19-40235367-G-A is described in ClinVar as [Benign]. Clinvar id is 1603051.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1823/152302) while in subpopulation AFR AF= 0.041 (1703/41554). AF 95% confidence interval is 0.0394. There are 35 homozygotes in gnomad4. There are 854 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1821 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT2	NM_001626.6	c.1176-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000392038.7
AKT2	NM_001243027.3	c.990-17C>T		splice_polypyrimidine_tract_variant, intron_variant
AKT2	NM_001243028.3	c.990-17C>T		splice_polypyrimidine_tract_variant, intron_variant
AKT2	NM_001330511.1	c.1047-17C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT2	ENST00000392038.7	c.1176-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001626.6	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1821 AN: 152184 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00333 AC: 833 AN: 250134 Hom.: 18 AF XY: 0.00267 AC XY: 362 AN XY: 135436

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00141 AC: 2059 AN: 1460676 Hom.: 26 Cov.: 31 AF XY: 0.00127 AC XY: 924 AN XY: 726686

Gnomad4 AFR exome AF: 0.0426

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000455

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.0120 AC: 1823 AN: 152302 Hom.: 35 Cov.: 32 AF XY: 0.0115 AC XY: 854 AN XY: 74470

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00695 Hom.: 3

Bravo AF: 0.0133

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Type 2 diabetes mellitus;C3278384:Hypoinsulinemic hypoglycemia and body hemihypertrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3730264; hg19: chr19-40741274;