NM_001382430.1:c.1260+98G>A

Variant names:

• chr14-104772267-C-T
• rs2498800
• NM_001382430.1:c.1260+98G>A

Variant summary

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

The NM_001382430.1(AKT1):​c.1260+98G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,280,700 control chromosomes in the GnomAD database, including 73,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8352 hom., cov: 33)
  • Exomes 𝑓: 0.33 (65137 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0790
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-104772267-C-T is Benign according to our data. Variant chr14-104772267-C-T is described in ClinVar as Benign. ClinVar VariationId is 1237020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382430.1. 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
	AKT1	NM_001382430.1	MANE Select	c.1260+98G>A		intron	N/A	NP_001369359.1
	AKT1	NM_001014431.2		c.1260+98G>A		intron	N/A	NP_001014431.1
	AKT1	NM_001014432.2		c.1260+98G>A		intron	N/A	NP_001014432.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.1260+98G>A		intron	N/A	ENSP00000497822.1
	AKT1	ENST00000349310.7	TSL:1	c.1260+98G>A		intron	N/A	ENSP00000270202.4
	AKT1	ENST00000402615.6	TSL:1	c.1260+98G>A		intron	N/A	ENSP00000385326.2

Frequencies

GnomAD3 genomes AF: 0.328 AC: 48903 AN: 149154 Hom.: 8354 Cov.: 33

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.332 AC: 375913 AN: 1131426 Hom.: 65137 Cov.: 15 AF XY: 0.335 AC XY: 191689 AN XY: 572398

African (AFR) AF: 0.266 AC: 7398 AN: 27766

American (AMR) AF: 0.502 AC: 21586 AN: 42962

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 6395 AN: 22430

East Asian (EAS) AF: 0.574 AC: 21861 AN: 38084

South Asian (SAS) AF: 0.450 AC: 33604 AN: 74604

European-Finnish (FIN) AF: 0.350 AC: 16684 AN: 47716

Middle Eastern (MID) AF: 0.359 AC: 1786 AN: 4974

European-Non Finnish (NFE) AF: 0.303 AC: 249734 AN: 823402

Other (OTH) AF: 0.341 AC: 16865 AN: 49488

GnomAD4 genome AF: 0.328 AC: 48938 AN: 149274 Hom.: 8352 Cov.: 33 AF XY: 0.335 AC XY: 24451 AN XY: 72956

African (AFR) AF: 0.268 AC: 11052 AN: 41266

American (AMR) AF: 0.435 AC: 6580 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 994 AN: 3434

East Asian (EAS) AF: 0.607 AC: 3121 AN: 5140

South Asian (SAS) AF: 0.488 AC: 2324 AN: 4766

European-Finnish (FIN) AF: 0.338 AC: 3434 AN: 10168

Middle Eastern (MID) AF: 0.317 AC: 92 AN: 290

European-Non Finnish (NFE) AF: 0.309 AC: 20436 AN: 66146

Other (OTH) AF: 0.329 AC: 686 AN: 2084

Alfa AF: 0.219 Hom.: 726

Bravo AF: 0.327

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	-0.90
CADD	Benign	1.4
DANN	Benign	0.84
PhyloP100		0.079
Mutation Taster		=100/0	polymorphism (auto)

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: rs2498800; hg19: chr14-105238604; COSMIC: COSV62574871; COSMIC: COSV62574871;