rs45559338

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-57561552-C-T
• chr20-57561552-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_002591.4(PCK1):​c.141C>T​(p.Asp47Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,613,912 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: PCK1 NM_002591.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.33
• Publications: 4 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 20-57561552-C-T is Benign according to our data. Variant chr20-57561552-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338870.
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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>T	p.Asp47Asp	synonymous	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>T	p.Asp47Asp	synonymous	Exon 2 of 10	ENSP00000319814.4	P35558-1
	PCK1	ENST00000467047.1	TSL:1	n.473C>T		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.141C>T	p.Asp47Asp	synonymous	Exon 1 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00146 AC: 368 AN: 251322 AF XY: 0.00155

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00254 AC: 3707 AN: 1461592 Hom.: 4 Cov.: 32 AF XY: 0.00253 AC XY: 1839 AN XY: 727098

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26136

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

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86256

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53302

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

European-Non Finnish (NFE) AF: 0.00306 AC: 3399 AN: 1111844

Other (OTH) AF: 0.00225 AC: 136 AN: 60390

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74492

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.00124 AC: 19 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68044

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Phosphoenolpyruvate carboxykinase deficiency, cytosolic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.10
DANN	Benign	0.46
PhyloP100		-1.3
PromoterAI		-0.066	Neutral
Mutation Taster		=286/14	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

dbSNP: rs45559338; hg19: chr20-56136608;