Genetic Variant PDK2:p.Val241Phe (chr17-50108191-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002611.5(PDK2):c.721G>T(p.Val241Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V241I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PDK2
NM_002611.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.05

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5 link	c.721G>T	p.Val241Phe	missense_variant	Exon 7 of 11	ENST00000503176.6	NP_002602.2	Q15119-1
PDK2	NM_001199898.2 link	c.529G>T	p.Val177Phe	missense_variant	Exon 8 of 12		NP_001186827.1	Q15119-2
PDK2	NM_001199899.2 link	c.529G>T	p.Val177Phe	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.721G>T	p.Val241Phe	missense_variant	Exon 7 of 11	1	NM_002611.5	ENSP00000420927.1		Q15119-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717578

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.0000235

AC:

AN:

42592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25684

East Asian (EAS)

AF:

0.00

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

83804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103050

Other (OTH)

AF:

0.00

AC:

AN:

59840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D;D;.;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.0

.;M;.;.;.

PhyloP100

8.1

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

D;D;D;.;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.88

MutPred

0.80

.;Loss of sheet (P = 0.0817);.;.;.;

MVP

0.91

MPC

1.6

ClinPred

1.0

GERP RS

4.6

Varity_R

0.95

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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17-50108191-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over