17-50108703-C-G

Variant names:

• chr17-50108703-C-G
• rs779847292
• NM_002611.5:c.953C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002611.5(PDK2):​c.953C>G​(p.Thr318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. T318I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0932301).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002611.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK2	NM_002611.5	MANE Select	c.953C>G	p.Thr318Ser	missense	Exon 9 of 11	NP_002602.2
	PDK2	NM_001199898.2		c.761C>G	p.Thr254Ser	missense	Exon 10 of 12	NP_001186827.1	Q15119-2
	PDK2	NM_001199899.2		c.761C>G	p.Thr254Ser	missense	Exon 9 of 11	NP_001186828.1	Q15119-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK2	ENST00000503176.6	TSL:1 MANE Select	c.953C>G	p.Thr318Ser	missense	Exon 9 of 11	ENSP00000420927.1	Q15119-1
	PDK2	ENST00000892669.1		c.1058C>G	p.Thr353Ser	missense	Exon 10 of 12	ENSP00000562728.1
	PDK2	ENST00000892667.1		c.998C>G	p.Thr333Ser	missense	Exon 10 of 12	ENSP00000562726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459542 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726014

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110622

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.048
Sift	Benign	0.82	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.35		Loss of solvent accessibility (P = 0.0576)
MVP		0.46
MPC		0.45
ClinPred		0.11	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.27

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

dbSNP: rs779847292; hg19: chr17-48186067;