dbSNP rs867812635: PDK2:p.Lys233Arg (chr17-50108168-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002611.5(PDK2):c.698A>G(p.Lys233Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,441,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PDK2
NM_002611.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.759

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08598721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5 link	c.698A>G	p.Lys233Arg	missense_variant	Exon 7 of 11	ENST00000503176.6	NP_002602.2	Q15119-1
PDK2	NM_001199898.2 link	c.506A>G	p.Lys169Arg	missense_variant	Exon 8 of 12		NP_001186827.1	Q15119-2
PDK2	NM_001199899.2 link	c.506A>G	p.Lys169Arg	missense_variant	Exon 7 of 11		NP_001186828.1	Q15119-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6 link	c.698A>G	p.Lys233Arg	missense_variant	Exon 7 of 11	1	NM_002611.5	ENSP00000420927.1		Q15119-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

221462

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1441862

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

715206

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33370

American (AMR)

AF:

0.00

AC:

AN:

42108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25610

East Asian (EAS)

AF:

0.00

AC:

AN:

39352

South Asian (SAS)

AF:

0.00

AC:

AN:

83224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100884

Other (OTH)

AF:

0.0000168

AC:

AN:

59690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.698A>G (p.K233R) alteration is located in exon 7 (coding exon 7) of the PDK2 gene. This alteration results from a A to G substitution at nucleotide position 698, causing the lysine (K) at amino acid position 233 to be replaced by an arginine (R). 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

Benign

0.062

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;T;.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.092

.;T;T;T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.086

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

.;N;.;.;.

PhyloP100

0.76

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.56

N;N;N;.;N

REVEL

Benign

0.067

Sift

Benign

0.30

T;T;T;.;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.0

.;B;.;.;.

Vest4

0.13

MutPred

0.35

.;Loss of ubiquitination at K233 (P = 0.0141);.;.;.;

MVP

0.48

MPC

0.41

ClinPred

0.037

GERP RS

0.97

Varity_R

0.11

gMVP

0.21

Mutation Taster

=86/14

polymorphism

(source)

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

Publications

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rs867812635

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over