NM_002611.5:c.883G>A

Variant names:

• chr17-50108633-G-A
• NM_002611.5:c.883G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002611.5(PDK2):​c.883G>A​(p.Val295Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31209847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5	c.883G>A	p.Val295Ile	missense_variant	Exon 9 of 11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2	c.691G>A	p.Val231Ile	missense_variant	Exon 10 of 12		NP_001186827.1
PDK2	NM_001199899.2	c.691G>A	p.Val231Ile	missense_variant	Exon 9 of 11		NP_001186828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6	c.883G>A	p.Val295Ile	missense_variant	Exon 9 of 11	1	NM_002611.5	ENSP00000420927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.883G>A (p.V295I) alteration is located in exon 9 (coding exon 9) of the PDK2 gene. This alteration results from a G to A substitution at nucleotide position 883, causing the valine (V) at amino acid position 295 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.21	.;T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.073
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	.;N;.;.
PhyloP100		10
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.26	N;N;N;.
REVEL	Benign	0.25
Sift	Benign	0.96	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0070	.;B;.;.
Vest4		0.47
MutPred		0.60		.;Loss of MoRF binding (P = 0.1112);.;.;
MVP		0.44
MPC		0.70
ClinPred		0.64	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.34

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

Other links and lift over

hg19: chr17-48185997;