17-50105970-A-C

Variant names:

• chr17-50105970-A-C
• rs1482552836
• NM_002611.5:c.418A>C

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.418A>C​(p.Thr140Pro) 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. 14/22 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. T140A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328
• 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=0.19246128).

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.418A>C	p.Thr140Pro	missense	Exon 4 of 11	NP_002602.2
	PDK2	NM_001199898.2		c.226A>C	p.Thr76Pro	missense	Exon 5 of 12	NP_001186827.1	Q15119-2
	PDK2	NM_001199899.2		c.226A>C	p.Thr76Pro	missense	Exon 4 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.418A>C	p.Thr140Pro	missense	Exon 4 of 11	ENSP00000420927.1	Q15119-1
	PDK2	ENST00000892669.1		c.523A>C	p.Thr175Pro	missense	Exon 5 of 12	ENSP00000562728.1
	PDK2	ENST00000892667.1		c.523A>C	p.Thr175Pro	missense	Exon 5 of 12	ENSP00000562726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.33
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.027	D
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.47
MutPred		0.41		Gain of disorder (P = 0.061)
MVP		0.26
MPC		0.69
ClinPred		0.087	T
GERP RS		0.18
Varity_R		0.78
gMVP		0.84

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: rs1482552836; hg19: chr17-48183334;