chr2-172566915-G-C

Position:

• chr2-172566915-G-C

Variant summary

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

The NM_002610.5(PDK1):​c.751G>C​(p.Glu251Gln) 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. 14/21 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)
• Consequence: PDK1 NM_002610.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

PDK1 (HGNC:8809): (pyruvate dehydrogenase kinase 1) Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2013]

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=0.19006366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDK1	NM_002610.5	c.751G>C	p.Glu251Gln	missense_variant	6/11	ENST00000282077.8	NP_002601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDK1	ENST00000282077.8	c.751G>C	p.Glu251Gln	missense_variant	6/11	1	NM_002610.5	ENSP00000282077	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.751G>C (p.E251Q) alteration is located in exon 6 (coding exon 6) of the PDK1 gene. This alteration results from a G to C substitution at nucleotide position 751, causing the glutamic acid (E) at amino acid position 251 to be replaced by a glutamine (Q). 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	0.070
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L;.;L;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.071	B;.;B;.
Vest4		0.28
MutPred		0.30		Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);.;
MVP		0.62
MPC		0.34
ClinPred		0.44	T
GERP RS		4.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.54

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-173431643;