NM_002612.4:c.400A>G

Variant names:

• chr7-95592889-T-C
• rs144262262
• NM_002612.4:c.400A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002612.4(PDK4):​c.400A>G​(p.Met134Val) variant causes a missense change. The variant allele was found at a frequency of 0.00508 in 1,612,224 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (75 hom.)
• Consequence: PDK4 NM_002612.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.22
• Publications: 10 publications found

Genes affected

PDK4 (HGNC:8812): (pyruvate dehydrogenase kinase 4) This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]

PDK4-AS1 (HGNC:55767): (PDK4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015191466).
• BP6: Variant 7-95592889-T-C is Benign according to our data. Variant chr7-95592889-T-C is described in ClinVar as Benign. ClinVar VariationId is 715405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00509 (7437/1459948) while in subpopulation MID AF = 0.0397 (229/5762). AF 95% confidence interval is 0.0355. There are 75 homozygotes in GnomAdExome4. There are 4063 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002612.4. 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
	PDK4	NM_002612.4	MANE Select	c.400A>G	p.Met134Val	missense	Exon 4 of 11	NP_002603.1	A4D1H4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK4	ENST00000005178.6	TSL:1 MANE Select	c.400A>G	p.Met134Val	missense	Exon 4 of 11	ENSP00000005178.5	Q16654
	PDK4	ENST00000886049.1		c.400A>G	p.Met134Val	missense	Exon 5 of 12	ENSP00000556108.1
	PDK4	ENST00000886050.1		c.394A>G	p.Met132Val	missense	Exon 4 of 11	ENSP00000556109.1

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 749 AN: 152158 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00668 AC: 1676 AN: 250810 AF XY: 0.00774

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00980

GnomAD4 exome AF: 0.00509 AC: 7437 AN: 1459948 Hom.: 75 Cov.: 29 AF XY: 0.00559 AC XY: 4063 AN XY: 726360

African (AFR) AF: 0.00153 AC: 51 AN: 33422

American (AMR) AF: 0.00468 AC: 209 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 1160 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0158 AC: 1358 AN: 86124

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53332

Middle Eastern (MID) AF: 0.0397 AC: 229 AN: 5762

European-Non Finnish (NFE) AF: 0.00353 AC: 3920 AN: 1110570

Other (OTH) AF: 0.00812 AC: 490 AN: 60308

GnomAD4 genome AF: 0.00491 AC: 748 AN: 152276 Hom.: 13 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74448

African (AFR) AF: 0.000842 AC: 35 AN: 41572

American (AMR) AF: 0.00882 AC: 135 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0161 AC: 78 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10620

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.00438 AC: 298 AN: 67986

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00679 Hom.: 24

Bravo AF: 0.00504

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00809

EpiControl AF: 0.00688

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.25
Sift	Benign	0.076	T
Sift4G	Benign	0.14	T
Polyphen		0.56	P
Vest4		0.84
MVP		0.47
MPC		0.48
ClinPred		0.040	T
GERP RS		5.5
Varity_R		0.73
gMVP		0.83
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144262262; hg19: chr7-95222201;