NM_002610.5:c.403A>G

Variant names:

• chr2-172562284-A-G
• rs1688694484
• NM_002610.5:c.403A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002610.5(PDK1):​c.403A>G​(p.Ile135Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDK1 NM_002610.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.603

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09351152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK1	NM_002610.5	c.403A>G	p.Ile135Val	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.403A>G	p.Ile135Val	missense_variant	Exon 3 of 11	1	NM_002610.5	ENSP00000282077.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431380 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 714086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.23	T;T;.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.58	.;.;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.094	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.64	.;N;N;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.80	N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.0	.;B;.;B;.
Vest4		0.24, 0.17, 0.20
MutPred		0.43		.;Loss of catalytic residue at I135 (P = 0.1004);Loss of catalytic residue at I135 (P = 0.1004);Loss of catalytic residue at I135 (P = 0.1004);.;
MVP		0.095
MPC		0.28
ClinPred		0.33	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.088

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: rs1688694484; hg19: chr2-173427012; COSMIC: COSV56375063; COSMIC: COSV56375063;