2-172562273-A-G

Variant names:

• chr2-172562273-A-G
• rs776618358
• NM_002610.5:c.392A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002610.5(PDK1):​c.392A>G​(p.Asp131Gly) 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDK1 NM_002610.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK1	NM_002610.5	c.392A>G	p.Asp131Gly	missense_variant	Exon 3 of 11	ENST00000282077.8	NP_002601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK1	ENST00000282077.8	c.392A>G	p.Asp131Gly	missense_variant	Exon 3 of 11	1	NM_002610.5	ENSP00000282077.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.6	.;M;M;M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		0.95	.;P;.;P;.
Vest4		0.49, 0.32, 0.34
MutPred		0.68		.;Loss of stability (P = 0.0765);Loss of stability (P = 0.0765);Loss of stability (P = 0.0765);.;
MVP		0.66
MPC		0.85
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.59

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

Other links and lift over

dbSNP: rs776618358; hg19: chr2-173427001;