14-104775041-C-T

Variant names:

• chr14-104775041-C-T
• rs3730346
• NM_001382430.1:c.567+35G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005163.2(AKT1):​c.567+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,082 control chromosomes in the GnomAD database, including 9,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (741 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8936 hom.)
• Consequence: AKT1 NM_005163.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.306
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-104775041-C-T is Benign according to our data. Variant chr14-104775041-C-T is described in ClinVar as Benign. ClinVar VariationId is 1282532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005163.2. 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.567+35G>A		intron	N/A	NP_001369359.1
	AKT1	NM_001014431.2		c.567+35G>A		intron	N/A	NP_001014431.1
	AKT1	NM_001014432.2		c.567+35G>A		intron	N/A	NP_001014432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.567+35G>A		intron	N/A	ENSP00000497822.1
	AKT1	ENST00000349310.7	TSL:1	c.567+35G>A		intron	N/A	ENSP00000270202.4
	AKT1	ENST00000402615.6	TSL:1	c.567+35G>A		intron	N/A	ENSP00000385326.2

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14246 AN: 151976 Hom.: 739 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0506

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0941 AC: 23549 AN: 250354 AF XY: 0.0947

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.107 AC: 156773 AN: 1460988 Hom.: 8936 Cov.: 32 AF XY: 0.106 AC XY: 77044 AN XY: 726750

African (AFR) AF: 0.0631 AC: 2113 AN: 33476

American (AMR) AF: 0.106 AC: 4735 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2730 AN: 26116

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39674

South Asian (SAS) AF: 0.0620 AC: 5351 AN: 86240

European-Finnish (FIN) AF: 0.110 AC: 5819 AN: 52970

Middle Eastern (MID) AF: 0.0809 AC: 466 AN: 5762

European-Non Finnish (NFE) AF: 0.116 AC: 129424 AN: 1111676

Other (OTH) AF: 0.101 AC: 6110 AN: 60368

GnomAD4 genome AF: 0.0938 AC: 14265 AN: 152094 Hom.: 741 Cov.: 32 AF XY: 0.0927 AC XY: 6892 AN XY: 74368

African (AFR) AF: 0.0634 AC: 2632 AN: 41494

American (AMR) AF: 0.109 AC: 1672 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 344 AN: 3466

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5178

South Asian (SAS) AF: 0.0508 AC: 244 AN: 4802

European-Finnish (FIN) AF: 0.109 AC: 1157 AN: 10618

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

European-Non Finnish (NFE) AF: 0.117 AC: 7925 AN: 67932

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.108 Hom.: 202

Bravo AF: 0.0945

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.79
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs3730346; hg19: chr14-105241378; COSMIC: COSV62573092;