chr2-172556233-T-G

Variant names:

• chr2-172556233-T-G
• NM_002610.5:c.83T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002610.5(PDK1):​c.83T>G​(p.Phe28Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDK1 NM_002610.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.345
• Publications: 0 publications found

Genes affected

PDK1 (HGNC:8809): (pyruvate dehydrogenase kinase 1) Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2013]

ITGA6-AS1 (HGNC:40308): (ITGA6 antisense RNA 1)

PDK1-AS1 (HGNC:40441): (PDK1 and ITGA6 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08710179).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002610.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK1	NM_002610.5	MANE Select	c.83T>G	p.Phe28Cys	missense	Exon 1 of 11	NP_002601.1	Q15118-1
	PDK1	NM_001278549.2		c.83T>G	p.Phe28Cys	missense	Exon 1 of 12	NP_001265478.1	Q15118-2
	PDK1	NR_103729.2		n.144T>G		non_coding_transcript_exon	Exon 1 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK1	ENST00000282077.8	TSL:1 MANE Select	c.83T>G	p.Phe28Cys	missense	Exon 1 of 11	ENSP00000282077.3	Q15118-1
	PDK1	ENST00000392571.6	TSL:1	c.83T>G	p.Phe28Cys	missense	Exon 1 of 12	ENSP00000376352.2	Q15118-2
	PDK1	ENST00000410055.5	TSL:1	c.83T>G	p.Phe28Cys	missense	Exon 1 of 12	ENSP00000386985.1	Q15118-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.69
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.34
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.042
Sift	Benign	0.035	D
Sift4G	Benign	0.14	T
Polyphen		0.044	B
Vest4		0.21
MutPred		0.24		Gain of glycosylation at S27 (P = 0.0491)
MVP		0.29
MPC		0.48
ClinPred		0.15	T
GERP RS		2.5
PromoterAI		-0.078	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.12
gMVP		0.34
Mutation Taster		=95/5	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

hg19: chr2-173420961;