17-50105970-A-G

Position:

• chr17-50105970-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002611.5(PDK2):​c.418A>G​(p.Thr140Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.328

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07881823).
• BP6: Variant 17-50105970-A-G is Benign according to our data. Variant chr17-50105970-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3210965.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK2	NM_002611.5	c.418A>G	p.Thr140Ala	missense_variant	4/11	ENST00000503176.6
PDK2	NM_001199898.2	c.226A>G	p.Thr76Ala	missense_variant	5/12
PDK2	NM_001199899.2	c.226A>G	p.Thr76Ala	missense_variant	4/11
PDK2	NM_001199900.2	c.418A>G	p.Thr140Ala	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK2	ENST00000503176.6	c.418A>G	p.Thr140Ala	missense_variant	4/11	1	NM_002611.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460260 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726198

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.7
DANN	Benign	0.86
DEOGEN2	Benign	0.19	.;.;T;T;T;.;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.53	.;T;T;T;T;T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	.;.;N;.;.;.;.;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.61	N;N;N;N;N;.;N;N
REVEL	Benign	0.017
Sift	Benign	0.52	T;T;T;T;T;.;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;.;.;.
Vest4		0.074
MutPred		0.37		.;.;Gain of catalytic residue at T140 (P = 0.0198);.;.;.;.;.;
MVP		0.18
MPC		0.49
ClinPred		0.041	T
GERP RS		0.18
Varity_R		0.18
gMVP		0.41

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: rs1482552836; hg19: chr17-48183334;