Variant 17-50108616-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000503176.6(PDK2):c.866G>A(p.Ser289Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PDK2
ENST00000503176.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55

Variant links:

Genes affected

PDK2 (HGNC:8810): (pyruvate dehydrogenase kinase 2) This gene encodes a member of the pyruvate dehydrogenase kinase family. The encoded protein phosphorylates pyruvate dehydrogenase, down-regulating the activity of the mitochondrial pyruvate dehydrogenase complex. Overexpression of this gene may play a role in both cancer and diabetes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

PDK2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PDK2	NM_002611.5 linkuse as main transcript	c.866G>A	p.Ser289Asn	missense_variant	9/11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2 linkuse as main transcript	c.674G>A	p.Ser225Asn	missense_variant	10/12		NP_001186827.1
PDK2	NM_001199899.2 linkuse as main transcript	c.674G>A	p.Ser225Asn	missense_variant	9/11		NP_001186828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6 linkuse as main transcript	c.866G>A	p.Ser289Asn	missense_variant	9/11	1	NM_002611.5	ENSP00000420927	P1	Q15119-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458048

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725096

show subpopulations

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:

0.00000631

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.866G>A (p.S289N) alteration is located in exon 9 (coding exon 9) of the PDK2 gene. This alteration results from a G to A substitution at nucleotide position 866, causing the serine (S) at amino acid position 289 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

.;D;D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.4

.;M;.;.

MutationTaster

Benign

0.82

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.7

D;D;D;.

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.85

.;P;.;.

Vest4

0.78

MutPred

0.60

.;Loss of phosphorylation at S289 (P = 0.0244);.;.;

MVP

0.69

MPC

1.2

ClinPred

0.99

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over