chr17-50110068-A-G

Position:

• chr17-50110068-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002611.5(PDK2):​c.1195A>G​(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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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]

ACMG classification

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
PDK2	NM_002611.5	c.1195A>G	p.Lys399Glu	missense_variant	11/11	ENST00000503176.6	NP_002602.2
SAMD14	NM_001257359.2	c.*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
PDK2	ENST00000503176.6	c.1195A>G	p.Lys399Glu	missense_variant	11/11	1	NM_002611.5	ENSP00000420927	P1
SAMD14	ENST00000330175.9	c.*2825T>C		3_prime_UTR_variant	10/10	1	NM_001257359.2	ENSP00000329144	P1

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The 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;