14-104772809-C-G

Variant names:

• chr14-104772809-C-G
• rs3803304
• NM_001382430.1:c.1172+69G>C

Variant summary

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

The ENST00000649815.2(AKT1):​c.1172+69G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,504,962 control chromosomes in the GnomAD database, including 49,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4572 hom., cov: 33)
  • Exomes 𝑓: 0.25 (45141 hom.)
• Consequence: AKT1 ENST00000649815.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.396
• Publications: 54 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=-0.82).
• BP6: Variant 14-104772809-C-G is Benign according to our data. Variant chr14-104772809-C-G is described in ClinVar as Benign. ClinVar VariationId is 1281623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

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.1172+69G>C		intron	N/A	NP_001369359.1
	AKT1	NM_001014431.2		c.1172+69G>C		intron	N/A	NP_001014431.1
	AKT1	NM_001014432.2		c.1172+69G>C		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.1172+69G>C		intron	N/A	ENSP00000497822.1
	AKT1	ENST00000349310.7	TSL:1	c.1172+69G>C		intron	N/A	ENSP00000270202.4
	AKT1	ENST00000402615.6	TSL:1	c.1172+69G>C		intron	N/A	ENSP00000385326.2

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36437 AN: 151674 Hom.: 4568 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0979

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.255 AC: 344850 AN: 1353172 Hom.: 45141 AF XY: 0.256 AC XY: 171210 AN XY: 667556

African (AFR) AF: 0.199 AC: 6224 AN: 31306

American (AMR) AF: 0.262 AC: 9360 AN: 35770

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5106 AN: 23076

East Asian (EAS) AF: 0.132 AC: 4845 AN: 36786

South Asian (SAS) AF: 0.312 AC: 23897 AN: 76626

European-Finnish (FIN) AF: 0.302 AC: 11031 AN: 36562

Middle Eastern (MID) AF: 0.257 AC: 1014 AN: 3938

European-Non Finnish (NFE) AF: 0.256 AC: 269283 AN: 1052664

Other (OTH) AF: 0.250 AC: 14090 AN: 56444

GnomAD4 genome AF: 0.240 AC: 36471 AN: 151790 Hom.: 4572 Cov.: 33 AF XY: 0.241 AC XY: 17907 AN XY: 74156

African (AFR) AF: 0.200 AC: 8288 AN: 41400

American (AMR) AF: 0.250 AC: 3817 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3470

East Asian (EAS) AF: 0.0980 AC: 503 AN: 5134

South Asian (SAS) AF: 0.312 AC: 1502 AN: 4814

European-Finnish (FIN) AF: 0.296 AC: 3120 AN: 10556

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17673 AN: 67852

Other (OTH) AF: 0.232 AC: 489 AN: 2104

Alfa AF: 0.245 Hom.: 580

Bravo AF: 0.233

Asia WGS AF: 0.203 AC: 709 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	-0.82
CADD	Benign	1.0
DANN	Benign	0.89
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs3803304; hg19: chr14-105239146; COSMIC: COSV62576115;