dbSNP rs148586321: PDK2:p.Arg291Gln (chr17-50108622-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002611.5(PDK2):c.872G>A(p.Arg291Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000493 in 1,611,360 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00094 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

PDK2
NM_002611.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01

Publications

3 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015206218).

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5 link	c.872G>A	p.Arg291Gln	missense_variant	Exon 9 of 11	ENST00000503176.6	NP_002602.2	Q15119-1
PDK2	NM_001199898.2 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 10 of 12		NP_001186827.1	Q15119-2
PDK2	NM_001199899.2 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 9 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.872G>A	p.Arg291Gln	missense_variant	Exon 9 of 11	1	NM_002611.5	ENSP00000420927.1		Q15119-1

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.0978

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000291

AC:

AN:

247568

AF XY:

0.000352

show subpopulations

Gnomad AFR exome

AF:

0.000445

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000499

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000446

AC:

651

AN:

1459274

Hom.:

Cov.:

AF XY:

0.000402

AC XY:

292

AN XY:

725710

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33448

American (AMR)

AF:

0.000158

AC:

AN:

44406

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85606

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000555

AC:

616

AN:

1110732

Other (OTH)

AF:

0.000182

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000940

AC:

143

AN:

152086

Hom.:

Cov.:

AF XY:

0.000969

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41394

American (AMR)

AF:

0.000589

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

67994

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000485

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000354

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.872G>A (p.R291Q) 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 872, causing the arginine (R) at amino acid position 291 to be replaced by a glutamine (Q). 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

0.071

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.83

.;T;T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.31

.;N;.;.

PhyloP100

4.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

N;N;N;.

REVEL

Benign

0.042

Sift

Benign

0.24

T;T;T;.

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.15

.;B;.;.

Vest4

0.33

MVP

0.55

MPC

0.65

ClinPred

0.030

GERP RS

2.9

Varity_R

0.24

gMVP

0.52

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over