chr17-50110068-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002611.5(PDK2):ā€‹c.1195A>Gā€‹(p.Lys399Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,854 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

PDK2
NM_002611.5 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.24
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25873506).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PDK2NM_002611.5 linkuse as main transcriptc.1195A>G p.Lys399Glu missense_variant 11/11 ENST00000503176.6 NP_002602.2
SAMD14NM_001257359.2 linkuse as main transcriptc.*2825T>C 3_prime_UTR_variant 10/10 ENST00000330175.9 NP_001244288.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PDK2ENST00000503176.6 linkuse as main transcriptc.1195A>G p.Lys399Glu missense_variant 11/111 NM_002611.5 ENSP00000420927 P1Q15119-1
SAMD14ENST00000330175.9 linkuse as main transcriptc.*2825T>C 3_prime_UTR_variant 10/101 NM_001257359.2 ENSP00000329144 P1Q8IZD0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1458854
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725518
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsApr 01, 2024The c.1195A>G (p.K399E) alteration is located in exon 11 (coding exon 11) of the PDK2 gene. This alteration results from a A to G substitution at nucleotide position 1195, causing the lysine (K) at amino acid position 399 to be replaced by a glutamic acid (E). 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
Uncertain
0.37
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
.;T;.
Eigen
Benign
0.030
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
.;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.7
.;L;.
MutationTaster
Benign
0.85
D;N;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.9
N;N;.
REVEL
Benign
0.18
Sift
Uncertain
0.020
D;D;.
Sift4G
Uncertain
0.060
T;T;T
Polyphen
0.16
.;B;.
Vest4
0.34
MutPred
0.23
.;Loss of ubiquitination at K399 (P = 0.0067);.;
MVP
0.60
MPC
0.87
ClinPred
0.83
D
GERP RS
4.5
Varity_R
0.25
gMVP
0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48187432; API