20-57561552-C-A

Variant names:

• chr20-57561552-C-A
• rs45559338
• NM_002591.4:c.141C>A

Variant summary

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

The NM_002591.4(PCK1):​c.141C>A​(p.Asp47Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D47D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCK1 NM_002591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 0 publications found

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]

PCK1 Gene-Disease associations (from GenCC):

• phosphoenolpyruvate carboxykinase deficiency, cytosolic

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• phosphoenolpyruvate carboxykinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002591.4. 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
	PCK1	NM_002591.4	MANE Select	c.141C>A	p.Asp47Glu	missense	Exon 2 of 10	NP_002582.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	ENST00000319441.6	TSL:1 MANE Select	c.141C>A	p.Asp47Glu	missense	Exon 2 of 10	ENSP00000319814.4	P35558-1
	PCK1	ENST00000467047.1	TSL:1	n.473C>A		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.141C>A	p.Asp47Glu	missense	Exon 1 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.020
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		-1.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.51	P
Vest4		0.59
MutPred		0.59		Gain of disorder (P = 0.092)
MVP		0.30
MPC		0.32
ClinPred		0.99	D
GERP RS		-1.9
PromoterAI		-0.071	Neutral
Varity_R		0.52
gMVP		0.76
Mutation Taster		=14/86	disease causing

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

dbSNP: rs45559338; hg19: chr20-56136608;