Genetic Variant NM_002611.5:c.418A>G (chr17-50105970-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_002611.5(PDK2):c.418A>G(p.Thr140Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PDK2
NM_002611.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.328

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07881823).

BP6

Variant 17-50105970-A-G is Benign according to our data. Variant chr17-50105970-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3210965.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5 link	c.418A>G	p.Thr140Ala	missense_variant	Exon 4 of 11	ENST00000503176.6	NP_002602.2	Q15119-1
PDK2	NM_001199898.2 link	c.226A>G	p.Thr76Ala	missense_variant	Exon 5 of 12		NP_001186827.1	Q15119-2
PDK2	NM_001199899.2 link	c.226A>G	p.Thr76Ala	missense_variant	Exon 4 of 11		NP_001186828.1	Q15119-2
PDK2	NM_001199900.2 link	c.418A>G	p.Thr140Ala	missense_variant	Exon 4 of 4		NP_001186829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6 link	c.418A>G	p.Thr140Ala	missense_variant	Exon 4 of 11	1	NM_002611.5	ENSP00000420927.1		Q15119-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460260

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726198

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111336

Other (OTH)

AF:

0.0000166

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 16, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.7

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.19

.;.;T;T;T;.;.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.53

.;T;T;T;T;T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.079

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.46

.;.;N;.;.;.;.;.

PhyloP100

0.33

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.61

N;N;N;N;N;.;N;N

REVEL

Benign

0.017

Sift

Benign

0.52

T;T;T;T;T;.;T;T

Sift4G

Benign

0.63

T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;B;.;.;.;.;.

Vest4

0.074

MutPred

0.37

.;.;Gain of catalytic residue at T140 (P = 0.0198);.;.;.;.;.;

MVP

0.18

MPC

0.49

ClinPred

0.041

GERP RS

0.18

Varity_R

0.18

gMVP

0.41

Mutation Taster

=73/27

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

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NM_002611.5:c.418A>G

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