20-57561545-T-C

Variant summary

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

The NM_002591.4(PCK1):c.134T>C(p.Ile45Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: PCK1 NM_002591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.52

Genes affected

PCK1 (HGNC:8724): (phosphoenolpyruvate carboxykinase 1) This gene is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. Defects in this gene are a cause of cytosolic phosphoenolpyruvate carboxykinase deficiency. A mitochondrial isozyme of the encoded protein also has been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCK1	NM_002591.4	c.134T>C	p.Ile45Thr	missense_variant	2/10	ENST00000319441.6
PCK1	XM_024451888.2	c.-81T>C		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCK1	ENST00000319441.6	c.134T>C	p.Ile45Thr	missense_variant	2/10	1	NM_002591.4	P1
PCK1	ENST00000467047.1	n.466T>C		non_coding_transcript_exon_variant	1/2	1
PCK1	ENST00000475833.1	n.275T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251348 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461618 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000316 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 07, 2018	The PCK1 c.134T>C (p.Ile45Thr) variant has been reported in one study and in one sibling pair from non-consanguineous parents, both in a homozygous state (Adams et al. 2014). Both the unaffected parents were heterozygous for the variant. The p.Ile45Thr variant is reported at a frequency of 0.001726 in the Ashkenazi Jewish population of the Genome Aggregation Database. PEPCK-C (cytosolic) and PEPCK-M (mitochondrial) activity was measured in frozen liver from one of the patients, who was found to have less than or equal to 10% of immuno-reactive PEPCK-C levels. Expression of the p.Ile45Thr variant protein in E.coli revealed it to be expressed as an insoluble protein largely located in inclusion bodies. The half-life of the p.Ile45Thr variant protein was two hours as compared to the 24 hour half-life of the wild type protein. The p.Ile45Thr variant did not affect mRNA stability. Based on the limited evidence, the p.Ile45Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for phosphoenolpyruvate carboxykinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.042	D
Polyphen		0.97	D
Vest4		0.80
MutPred		0.68		Loss of stability (P = 0.0291);
MVP		0.68
MPC		0.54
ClinPred		0.58	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs202197769; hg19: chr20-56136601;