17-50108168-A-G

Variant names:

• chr17-50108168-A-G
• rs867812635
• NM_002611.5:c.698A>G

Variant summary

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

The NM_002611.5(PDK2):​c.698A>G​(p.Lys233Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,441,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.759

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

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=0.08598721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5	c.698A>G	p.Lys233Arg	missense_variant	Exon 7 of 11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2	c.506A>G	p.Lys169Arg	missense_variant	Exon 8 of 12		NP_001186827.1
PDK2	NM_001199899.2	c.506A>G	p.Lys169Arg	missense_variant	Exon 7 of 11		NP_001186828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6	c.698A>G	p.Lys233Arg	missense_variant	Exon 7 of 11	1	NM_002611.5	ENSP00000420927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1441862 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 715206

Gnomad4 AFR exome AF: 0.0000899

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: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.698A>G (p.K233R) alteration is located in exon 7 (coding exon 7) of the PDK2 gene. This alteration results from a A to G substitution at nucleotide position 698, causing the lysine (K) at amino acid position 233 to be replaced by an arginine (R). 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	0.062
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;T;.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.092	.;T;T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.086	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	.;N;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.56	N;N;N;.;N
REVEL	Benign	0.067
Sift	Benign	0.30	T;T;T;.;T
Sift4G	Benign	0.66	T;T;T;T;T
Polyphen		0.0	.;B;.;.;.
Vest4		0.13
MutPred		0.35		.;Loss of ubiquitination at K233 (P = 0.0141);.;.;.;
MVP		0.48
MPC		0.41
ClinPred		0.037	T
GERP RS		0.97
Varity_R		0.11
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs867812635; hg19: chr17-48185532;