14-104780120-C-G

Variant names:

• chr14-104780120-C-G
• NM_001382430.1:c.143G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382430.1(AKT1):​c.143G>C​(p.Arg48Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AKT1 NM_001382430.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25599027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.143G>C	p.Arg48Pro	missense_variant	Exon 4 of 15	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.143G>C	p.Arg48Pro	missense_variant	Exon 4 of 15		NM_001382430.1	ENSP00000497822.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461356 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0062	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Uncertain	0.60	D;D;D;D;D;D;D;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	.;.;.;.;.;.;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N;N;.;N;N
REVEL	Benign	0.26
Sift	Benign	0.30	T;T;T;T;T;.;T;T
Sift4G	Benign	0.29	T;T;T;T;T;.;T;.
Polyphen		0.028	B;B;B;B;B;B;B;.
Vest4		0.63
MutPred		0.49		Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);Gain of catalytic residue at L52 (P = 0.0867);
MVP		0.71
MPC		2.2
ClinPred		0.66	D
GERP RS		0.44
Varity_R		0.75
gMVP		0.61

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105246457;