chr17-50108622-G-A

Variant names:

• chr17-50108622-G-A
• rs148586321
• NM_002611.5:c.872G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002611.5(PDK2):​c.872G>A​(p.Arg291Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000493 in 1,611,360 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• Publications: 3 publications found

Genes affected

PDK2 (HGNC:8810): (pyruvate dehydrogenase kinase 2) This gene encodes a member of the pyruvate dehydrogenase kinase family. The encoded protein phosphorylates pyruvate dehydrogenase, down-regulating the activity of the mitochondrial pyruvate dehydrogenase complex. Overexpression of this gene may play a role in both cancer and diabetes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015206218).
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5	c.872G>A	p.Arg291Gln	missense_variant	Exon 9 of 11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2	c.680G>A	p.Arg227Gln	missense_variant	Exon 10 of 12		NP_001186827.1
PDK2	NM_001199899.2	c.680G>A	p.Arg227Gln	missense_variant	Exon 9 of 11		NP_001186828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6	c.872G>A	p.Arg291Gln	missense_variant	Exon 9 of 11	1	NM_002611.5	ENSP00000420927.1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152086 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.000589

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: 0.000456

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000291 AC: 72 AN: 247568 AF XY: 0.000352

Gnomad AFR exome AF: 0.000445

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000446 AC: 651 AN: 1459274 Hom.: 0 Cov.: 32 AF XY: 0.000402 AC XY: 292 AN XY: 725710

African (AFR) AF: 0.000389 AC: 13 AN: 33448

American (AMR) AF: 0.000158 AC: 7 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85606

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53314

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000555 AC: 616 AN: 1110732

Other (OTH) AF: 0.000182 AC: 11 AN: 60306

GnomAD4 genome AF: 0.000940 AC: 143 AN: 152086 Hom.: 5 Cov.: 31 AF XY: 0.000969 AC XY: 72 AN XY: 74294

African (AFR) AF: 0.000314 AC: 13 AN: 41394

American (AMR) AF: 0.000589 AC: 9 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67994

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.00135

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.872G>A (p.R291Q) alteration is located in exon 9 (coding exon 9) of the PDK2 gene. This alteration results from a G to A substitution at nucleotide position 872, causing the arginine (R) at amino acid position 291 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	0.071
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.31	.;N;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Benign	0.042
Sift	Benign	0.24	T;T;T;.
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.15	.;B;.;.
Vest4		0.33
MVP		0.55
MPC		0.65
ClinPred		0.030	T
GERP RS		2.9
Varity_R		0.24
gMVP		0.52
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs148586321; hg19: chr17-48185986;