rs56217512

Variant names:

• chr14-104792635-G-A
• rs56217512
• NM_001382430.1:c.9C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001382430.1(AKT1):​c.9C>T​(p.Asp3Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,611,060 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: AKT1 NM_001382430.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.67
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-104792635-G-A is Benign according to our data. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104792635-G-A is described in CliVar as Likely_benign. Clinvar id is 473867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000985 (15/152266) while in subpopulation EAS AF = 0.00251 (13/5174). AF 95% confidence interval is 0.00149. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.9C>T	p.Asp3Asp	synonymous_variant	Exon 3 of 15	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.9C>T	p.Asp3Asp	synonymous_variant	Exon 3 of 15		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248402 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000234 AC: 342 AN: 1458794 Hom.: 2 Cov.: 32 AF XY: 0.000222 AC XY: 161 AN XY: 725866

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00768 AC: 305 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111864

Other (OTH) AF: 0.0000331 AC: 2 AN: 60350

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74450

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Mar 16, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cowden syndrome 6 Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		2.7
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)		0.010		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: rs56217512; hg19: chr14-105258972;