rs1250656724

Variant names:

• chrX-24527621-C-A
• rs1250656724
• NM_005391.5:c.798C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_005391.5(PDK3):​c.798C>A​(p.Gly266Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,194,484 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 1 hem.)
• Consequence: PDK3 NM_005391.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.245
• Publications: 0 publications found

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]

PDK3 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 6

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-24527621-C-A is Benign according to our data. Variant chrX-24527621-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.245 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005391.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	NM_005391.5	MANE Select	c.798C>A	p.Gly266Gly	synonymous	Exon 8 of 11	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.798C>A	p.Gly266Gly	synonymous	Exon 8 of 12	NP_001135858.1	Q15120-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	ENST00000379162.9	TSL:1 MANE Select	c.798C>A	p.Gly266Gly	synonymous	Exon 8 of 11	ENSP00000368460.4	Q15120-1
	PDK3	ENST00000568479.2	TSL:6	c.798C>A	p.Gly266Gly	synonymous	Exon 8 of 12	ENSP00000498864.1	Q15120-2
	PDK3	ENST00000862654.1		c.798C>A	p.Gly266Gly	synonymous	Exon 8 of 10	ENSP00000532713.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112052 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000585 AC: 1 AN: 171040 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000102 AC: 11 AN: 1082432 Hom.: 0 Cov.: 25 AF XY: 0.00000286 AC XY: 1 AN XY: 349482

African (AFR) AF: 0.00 AC: 0 AN: 26065

American (AMR) AF: 0.00 AC: 0 AN: 34421

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19146

East Asian (EAS) AF: 0.00 AC: 0 AN: 30055

South Asian (SAS) AF: 0.00 AC: 0 AN: 52570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.0000120 AC: 10 AN: 830231

Other (OTH) AF: 0.0000220 AC: 1 AN: 45506

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112052 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34212

African (AFR) AF: 0.00 AC: 0 AN: 30872

American (AMR) AF: 0.00 AC: 0 AN: 10522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3619

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53222

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease X-linked dominant 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.4
DANN	Benign	0.53
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs1250656724; hg19: chrX-24545738;