X-24465574-C-CCA

Variant names:

• chrX-24465574-C-CCA
• rs1940055207
• NM_005391.5:c.106+14_106+15dupCA

Variant summary

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

The NM_005391.5(PDK3):​c.106+14_106+15dupCA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: PDK3 NM_005391.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

PDK3 (HGNC:8811): (pyruvate dehydrogenase kinase 3) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the three pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 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
PDK3	NM_005391.5	c.106+14_106+15dupCA		intron_variant	Intron 1 of 10	ENST00000379162.9	NP_005382.1
PDK3	NM_001142386.3	c.106+14_106+15dupCA		intron_variant	Intron 1 of 11		NP_001135858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK3	ENST00000379162.9	c.106+13_106+14insCA		intron_variant	Intron 1 of 10	1	NM_005391.5	ENSP00000368460.4
PDK3	ENST00000568479.2	c.106+13_106+14insCA		intron_variant	Intron 1 of 11	6		ENSP00000498864.1
PDK3	ENST00000493226.2	n.318+13_318+14insCA		intron_variant	Intron 1 of 2	5
PDK3	ENST00000648777.1	n.106+13_106+14insCA		intron_variant	Intron 1 of 11			ENSP00000497727.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6 Uncertain:1

Oct 29, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1940055207; hg19: chrX-24483691;