chr17-50110086-C-T

Position:

chr17-50110086-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002611.5(PDK2):c.1213C>T(p.Arg405Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,605,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PDK2
NM_002611.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.21

Variant links:

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]

PDK2 links:

SAMD14 (HGNC:27312): (sterile alpha motif domain containing 14) Predicted to enable actin filament binding activity. Predicted to be involved in actin filament organization; calcium-mediated signaling; and neuron projection development. Predicted to be active in several cellular components, including actin cytoskeleton; dendrite; and postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

SAMD14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35098848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDK2	NM_002611.5 linkuse as main transcript	c.1213C>T	p.Arg405Cys	missense_variant	11/11	ENST00000503176.6	NP_002602.2
SAMD14	NM_001257359.2 linkuse as main transcript	c.*2807G>A		3_prime_UTR_variant	10/10	ENST00000330175.9	NP_001244288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6 linkuse as main transcript	c.1213C>T	p.Arg405Cys	missense_variant	11/11	1	NM_002611.5	ENSP00000420927	P1	Q15119-1
SAMD14	ENST00000330175.9 linkuse as main transcript	c.*2807G>A		3_prime_UTR_variant	10/10	1	NM_001257359.2	ENSP00000329144	P1	Q8IZD0-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

241944

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1453594

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.1213C>T (p.R405C) alteration is located in exon 11 (coding exon 11) of the PDK2 gene. This alteration results from a C to T substitution at nucleotide position 1213, causing the arginine (R) at amino acid position 405 to be replaced by a cysteine (C). 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

0.25

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

.;D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.9

D;D;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.0010

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.48

MutPred

0.36

.;Gain of sheet (P = 0.0028);.;

MVP

0.67

MPC

1.5

ClinPred

0.97

GERP RS

4.5

Varity_R

0.28

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over