chr8-93917811-T-TGCCGCCGCCTCCTC

Position:

• chr8-93917811-T-TGCCGCCGCCTCCTC

Variant summary

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

The NM_018444.4(PDP1):​c.-45+732_-45+733insGCCGCCGCCTCCTC 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 (★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDP1 NM_018444.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

PDP1 (HGNC:9279): (pyruvate dehydrogenase phosphatase catalytic subunit 1) Pyruvate dehydrogenase (E1) is one of the three components (E1, E2, and E3) of the large pyruvate dehydrogenase complex. Pyruvate dehydrogenase kinases catalyze phosphorylation of serine residues of E1 to inactivate the E1 component and inhibit the complex. Pyruvate dehydrogenase phosphatases catalyze the dephosphorylation and activation of the E1 component to reverse the effects of pyruvate dehydrogenase kinases. Pyruvate dehydrogenase phosphatase is a heterodimer consisting of catalytic and regulatory subunits. Two catalytic subunits have been reported; one is predominantly expressed in skeletal muscle and another one is is much more abundant in the liver. The catalytic subunit, encoded by this gene, is the former, and belongs to the protein phosphatase 2C (PP2C) superfamily. Along with the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinases, this enzyme is located in the mitochondrial matrix. Mutation in this gene causes pyruvate dehydrogenase phosphatase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Jun 2009]

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/exons	MANE	Protein	UniProt
PDP1	NM_018444.4	c.-45+732_-45+733insGCCGCCGCCTCCTC		intron_variant		ENST00000297598.5	NP_060914.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDP1	ENST00000297598.5	c.-45+732_-45+733insGCCGCCGCCTCCTC		intron_variant		1	NM_018444.4	ENSP00000297598	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

GeneDx

Jun 19, 2013

NM_018444.3;IVS1+732_IVS1+733insGCCGCCGCCTCCTC;c.-45+732_-45+733insGCCGCCGCCTCCTC. A variant of unknown significance has been identified in the PDP1 gene. The c.-45+732_-45+733insGCCGCCGCCTCCTC variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Mutations in the promoter region of the PDP1 gene have not been reported previously to our knowledge. We can not predict what effect c.-45+732_-45+733insGCCGCCGCCTCCTC may have on the transcription of the gene or the resultant protein. Therefore, based on the currently available information, it is unclear whether c.-45+732_-45+733insGCCGCCGCCTCCTC is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		8.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224159; hg19: chr8-94930039;