chr17-50108412-A-C

Variant names:

• chr17-50108412-A-C
• rs770323108
• NM_002611.5:c.856A>C

Variant summary

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

The NM_002611.5(PDK2):​c.856A>C​(p.Ile286Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I286V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5	c.856A>C	p.Ile286Leu	missense_variant	Exon 8 of 11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2	c.664A>C	p.Ile222Leu	missense_variant	Exon 9 of 12		NP_001186827.1
PDK2	NM_001199899.2	c.664A>C	p.Ile222Leu	missense_variant	Exon 8 of 11		NP_001186828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6	c.856A>C	p.Ile286Leu	missense_variant	Exon 8 of 11	1	NM_002611.5	ENSP00000420927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0080	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	.;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	D;D;D;.
Sift4G	Uncertain	0.043	D;D;D;D
Polyphen		0.015	.;B;.;.
Vest4		0.56
MutPred		0.73		.;Loss of ubiquitination at K287 (P = 0.065);.;.;
MVP		0.57
MPC		1.4
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs770323108; hg19: chr17-48185776;