17-50108392-T-C

Variant names:

• chr17-50108392-T-C
• NM_002611.5:c.836T>C

Variant summary

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

The NM_002611.5(PDK2):​c.836T>C​(p.Leu279Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.28
• 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 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.836T>C	p.Leu279Ser	missense_variant	Exon 8 of 11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2	c.644T>C	p.Leu215Ser	missense_variant	Exon 9 of 12		NP_001186827.1
PDK2	NM_001199899.2	c.644T>C	p.Leu215Ser	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.836T>C	p.Leu279Ser	missense_variant	Exon 8 of 11	1	NM_002611.5	ENSP00000420927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.836T>C (p.L279S) alteration is located in exon 8 (coding exon 8) of the PDK2 gene. This alteration results from a T to C substitution at nucleotide position 836, causing the leucine (L) at amino acid position 279 to be replaced by a serine (S). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.95	.;L;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D;D;D;.
REVEL	Uncertain	0.42
Sift	Benign	0.33	T;T;T;.
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.89	.;P;.;.
Vest4		0.79
MutPred		0.46		.;Gain of disorder (P = 0.0058);.;.;
MVP		0.77
MPC		1.7
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.40
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr17-48185756;