14-104772374-G-A

Variant names:

• chr14-104772374-G-A
• rs139297659
• NM_001382430.1:c.1251C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000649815.2(AKT1):​c.1251C>T​(p.Tyr417Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,818 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.012 (151 hom.)
• Consequence: AKT1 ENST00000649815.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.374
• Publications: 9 publications found

Genes affected

AKT1 (HGNC:391): (AKT serine/threonine kinase 1) This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

AKT1 Gene-Disease associations (from GenCC):

• Proteus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 6

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-104772374-G-A is Benign according to our data. Variant chr14-104772374-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.374 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0103 (1572/152306) while in subpopulation SAS AF = 0.0195 (94/4818). AF 95% confidence interval is 0.0163. There are 12 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1572 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649815.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	NM_001382430.1	MANE Select	c.1251C>T	p.Tyr417Tyr	synonymous	Exon 13 of 15	NP_001369359.1
	AKT1	NM_001014431.2		c.1251C>T	p.Tyr417Tyr	synonymous	Exon 12 of 14	NP_001014431.1
	AKT1	NM_001014432.2		c.1251C>T	p.Tyr417Tyr	synonymous	Exon 13 of 15	NP_001014432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.1251C>T	p.Tyr417Tyr	synonymous	Exon 13 of 15	ENSP00000497822.1
	AKT1	ENST00000349310.7	TSL:1	c.1251C>T	p.Tyr417Tyr	synonymous	Exon 13 of 15	ENSP00000270202.4
	AKT1	ENST00000402615.6	TSL:1	c.1251C>T	p.Tyr417Tyr	synonymous	Exon 12 of 14	ENSP00000385326.2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1572 AN: 152188 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00837

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0120 AC: 3024 AN: 251258 AF XY: 0.0123

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0124 AC: 18060 AN: 1461512 Hom.: 151 Cov.: 32 AF XY: 0.0125 AC XY: 9091 AN XY: 727082

African (AFR) AF: 0.00215 AC: 72 AN: 33480

American (AMR) AF: 0.00736 AC: 329 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 333 AN: 26136

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

South Asian (SAS) AF: 0.0160 AC: 1377 AN: 86258

European-Finnish (FIN) AF: 0.0112 AC: 593 AN: 53098

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14591 AN: 1111968

Other (OTH) AF: 0.0118 AC: 714 AN: 60392

GnomAD4 genome AF: 0.0103 AC: 1572 AN: 152306 Hom.: 12 Cov.: 33 AF XY: 0.0101 AC XY: 754 AN XY: 74472

African (AFR) AF: 0.00233 AC: 97 AN: 41574

American (AMR) AF: 0.00836 AC: 128 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4818

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1031 AN: 68016

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0129 Hom.: 5

Bravo AF: 0.00930

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0148

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Cowden syndrome 6 (2)
-	-	1	AKT1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.95
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs139297659; hg19: chr14-105238711; COSMIC: COSV104422037;