2-172564513-A-T

Variant names:

• chr2-172564513-A-T
• rs763810546
• NM_002610.5:c.421A>T

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.421A>T​(p.Thr141Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T141P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDK1 NM_002610.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.72
• 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]

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=0.19150504).

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.421A>T	p.Thr141Ser	missense	Exon 4 of 11	NP_002601.1	Q15118-1
	PDK1	NM_001278549.2		c.481A>T	p.Thr161Ser	missense	Exon 5 of 12	NP_001265478.1	Q15118-2
	PDK1	NR_103729.2		n.482A>T		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK1	ENST00000282077.8	TSL:1 MANE Select	c.421A>T	p.Thr141Ser	missense	Exon 4 of 11	ENSP00000282077.3	Q15118-1
	PDK1	ENST00000392571.6	TSL:1	c.481A>T	p.Thr161Ser	missense	Exon 5 of 12	ENSP00000376352.2	Q15118-2
	PDK1	ENST00000410055.5	TSL:1	c.421A>T	p.Thr141Ser	missense	Exon 4 of 12	ENSP00000386985.1	Q15118-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250528 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460092 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726228

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110916

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.066
Sift	Benign	0.33	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.49
MutPred		0.47		Gain of helix (P = 0.132)
MVP		0.35
MPC		0.37
ClinPred		0.30	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.49
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

dbSNP: rs763810546; hg19: chr2-173429241;