7-95589703-G-C

Position:

• chr7-95589703-G-C

Variant summary

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

The NM_002612.4(PDK4):​c.708C>G​(p.Asp236Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDK4 NM_002612.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

Genes affected

PDK4 (HGNC:8812): (pyruvate dehydrogenase kinase 4) This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]

PDK4 (HGNC:):

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=0.1355814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDK4	NM_002612.4	c.708C>G	p.Asp236Glu	missense_variant	7/11	ENST00000005178.6	NP_002603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDK4	ENST00000005178.6	c.708C>G	p.Asp236Glu	missense_variant	7/11	1	NM_002612.4	ENSP00000005178.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Oct 07, 2024

The c.708C>G (p.D236E) alteration is located in exon 7 (coding exon 7) of the PDK4 gene. This alteration results from a C to G substitution at nucleotide position 708, causing the aspartic acid (D) at amino acid position 236 to be replaced by a glutamic acid (E). 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	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.073
Sift	Benign	0.14	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.28		Loss of ubiquitination at K233 (P = 0.065);
MVP		0.48
MPC		0.086
ClinPred		0.17	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs771679623; hg19: chr7-95219015;