14-104774967-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001382430.1(AKT1):​c.604C>T​(p.Leu202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,612,822 control chromosomes in the GnomAD database, including 676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L202L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.036 ( 337 hom., cov: 33)
Exomes 𝑓: 0.0040 ( 339 hom. )

Consequence

AKT1
NM_001382430.1 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 14-104774967-G-A is Benign according to our data. Variant chr14-104774967-G-A is described in ClinVar as [Benign]. Clinvar id is 416469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104774967-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AKT1NM_001382430.1 linkuse as main transcriptc.604C>T p.Leu202= synonymous_variant 8/15 ENST00000649815.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AKT1ENST00000649815.2 linkuse as main transcriptc.604C>T p.Leu202= synonymous_variant 8/15 NM_001382430.1 P1P31749-1

Frequencies

GnomAD3 genomes
AF:
0.0359
AC:
5461
AN:
151982
Hom.:
337
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.125
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0123
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000831
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.0263
GnomAD3 exomes
AF:
0.00969
AC:
2425
AN:
250248
Hom.:
146
AF XY:
0.00707
AC XY:
957
AN XY:
135302
show subpopulations
Gnomad AFR exome
AF:
0.127
Gnomad AMR exome
AF:
0.00666
Gnomad ASJ exome
AF:
0.000598
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.000330
Gnomad NFE exome
AF:
0.000637
Gnomad OTH exome
AF:
0.00540
GnomAD4 exome
AF:
0.00396
AC:
5791
AN:
1460722
Hom.:
339
Cov.:
31
AF XY:
0.00346
AC XY:
2513
AN XY:
726678
show subpopulations
Gnomad4 AFR exome
AF:
0.132
Gnomad4 AMR exome
AF:
0.00770
Gnomad4 ASJ exome
AF:
0.000689
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000302
Gnomad4 FIN exome
AF:
0.000247
Gnomad4 NFE exome
AF:
0.000342
Gnomad4 OTH exome
AF:
0.00886
GnomAD4 genome
AF:
0.0359
AC:
5463
AN:
152100
Hom.:
337
Cov.:
33
AF XY:
0.0340
AC XY:
2531
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.125
Gnomad4 AMR
AF:
0.0123
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000832
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000603
Gnomad4 OTH
AF:
0.0261
Alfa
AF:
0.0164
Hom.:
66
Bravo
AF:
0.0413
Asia WGS
AF:
0.00635
AC:
22
AN:
3478
EpiCase
AF:
0.000818
EpiControl
AF:
0.000831

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Cowden syndrome 6 Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxApr 03, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
CADD
Benign
17
DANN
Benign
0.75
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.25
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.25
Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2230506; hg19: chr14-105241304; COSMIC: COSV104422011; COSMIC: COSV104422011; API