Genetic Variant PDK1:p.Asp131Ala (chr2-172562273-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002610.5(PDK1):c.392A>C(p.Asp131Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D131V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PDK1
NM_002610.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.86

Publications

1 publications found

Variant links:

Genes affected

PDK1 (HGNC:8809): (pyruvate dehydrogenase kinase 1) Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2013]

PDK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002610.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDK1	NM_002610.5	MANE Select	c.392A>C	p.Asp131Ala	missense	Exon 3 of 11	NP_002601.1	Q15118-1
PDK1	NM_001278549.2		c.392A>C	p.Asp131Ala	missense	Exon 3 of 12	NP_001265478.1	Q15118-2
PDK1	NR_103729.2		n.453A>C		non_coding_transcript_exon	Exon 3 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDK1	ENST00000282077.8	TSL:1 MANE Select	c.392A>C	p.Asp131Ala	missense	Exon 3 of 11	ENSP00000282077.3	Q15118-1
PDK1	ENST00000392571.6	TSL:1	c.392A>C	p.Asp131Ala	missense	Exon 3 of 12	ENSP00000376352.2	Q15118-2
PDK1	ENST00000410055.5	TSL:1	c.392A>C	p.Asp131Ala	missense	Exon 3 of 12	ENSP00000386985.1	Q15118-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250892

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.0032

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

PhyloP100

5.9

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.7

REVEL

Benign

0.24

Sift

Benign

0.036

Sift4G

Uncertain

0.040

Polyphen

0.92

Vest4

0.62

MutPred

0.66

Loss of disorder (P = 0.0762)

MVP

0.58

MPC

0.90

ClinPred

0.95

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.61

Mutation Taster

=36/64

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over