17-50108622-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/21 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

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons MANE Protein UniProt
PDK2NM_002611.5 linkuse as main transcriptc.872G>A p.Arg291Gln missense_variant 9/11 ENST00000503176.6 NP_002602.2
PDK2NM_001199898.2 linkuse as main transcriptc.680G>A p.Arg227Gln missense_variant 10/12 NP_001186827.1
PDK2NM_001199899.2 linkuse as main transcriptc.680G>A p.Arg227Gln missense_variant 9/11 NP_001186828.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PDK2ENST00000503176.6 linkuse as main transcriptc.872G>A p.Arg291Gln missense_variant 9/111 NM_002611.5 ENSP00000420927 P1Q15119-1

Frequencies

GnomAD3 genomes
AF:
0.000940
AC:
143
AN:
152086
Hom.:
5
Cov.:
31
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
GnomAD3 exomes
AF:
0.000291
AC:
72
AN:
247568
Hom.:
0
AF XY:
0.000352
AC XY:
47
AN XY:
133684
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 SAS exome
AF:
0.0000335
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.:
0
Cov.:
32
AF XY:
0.000402
AC XY:
292
AN XY:
725710
show subpopulations
Gnomad4 AFR exome
AF:
0.000389
Gnomad4 AMR exome
AF:
0.000158
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.000555
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000940
AC:
143
AN:
152086
Hom.:
5
Cov.:
31
AF XY:
0.000969
AC XY:
72
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.000314
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000456
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000509
Hom.:
0
Bravo
AF:
0.00135
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000354
AC:
43

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 submitterclinical testingAmbry GeneticsAug 09, 2021The 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
T
BayesDel_noAF
Benign
-0.45
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
.;T;T;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.17
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.83
.;T;T;T
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.015
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.31
.;N;.;.
MutationTaster
Benign
0.98
D;D
PrimateAI
Uncertain
0.59
T
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
T
GERP RS
2.9
Varity_R
0.24
gMVP
0.52

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

LitVar

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

Other links and lift over

dbSNP: rs148586321; hg19: chr17-48185986; API