NM_002591.4:c.1319-129C>T

Variant names:

• chr20-57564911-C-T
• rs1023049
• NM_002591.4:c.1319-129C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002591.4(PCK1):​c.1319-129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 755,900 control chromosomes in the GnomAD database, including 73,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13729 hom., cov: 33)
  • Exomes 𝑓: 0.44 (59748 hom.)
• Consequence: PCK1 NM_002591.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-57564911-C-T is Benign according to our data. Variant chr20-57564911-C-T is described in ClinVar as Benign. ClinVar VariationId is 1181378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	NM_002591.4	MANE Select	c.1319-129C>T		intron	N/A	NP_002582.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	ENST00000319441.6	TSL:1 MANE Select	c.1319-129C>T		intron	N/A	ENSP00000319814.4
	PCK1	ENST00000467047.1	TSL:1	n.3832C>T		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.1319-129C>T		intron	N/A	ENSP00000521968.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63793 AN: 151968 Hom.: 13718 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.404

GnomAD4 exome AF: 0.441 AC: 266387 AN: 603814 Hom.: 59748 Cov.: 8 AF XY: 0.439 AC XY: 138643 AN XY: 315982

African (AFR) AF: 0.355 AC: 5607 AN: 15802

American (AMR) AF: 0.506 AC: 12085 AN: 23868

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 6359 AN: 15238

East Asian (EAS) AF: 0.651 AC: 22759 AN: 34960

South Asian (SAS) AF: 0.405 AC: 21090 AN: 52132

European-Finnish (FIN) AF: 0.451 AC: 20931 AN: 46408

Middle Eastern (MID) AF: 0.346 AC: 861 AN: 2488

European-Non Finnish (NFE) AF: 0.428 AC: 163233 AN: 381792

Other (OTH) AF: 0.432 AC: 13462 AN: 31126

GnomAD4 genome AF: 0.420 AC: 63851 AN: 152086 Hom.: 13729 Cov.: 33 AF XY: 0.424 AC XY: 31512 AN XY: 74348

African (AFR) AF: 0.359 AC: 14899 AN: 41462

American (AMR) AF: 0.470 AC: 7187 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1475 AN: 3470

East Asian (EAS) AF: 0.650 AC: 3362 AN: 5174

South Asian (SAS) AF: 0.416 AC: 2007 AN: 4820

European-Finnish (FIN) AF: 0.440 AC: 4655 AN: 10576

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28993 AN: 67978

Other (OTH) AF: 0.407 AC: 860 AN: 2114

Alfa AF: 0.419 Hom.: 18032

Bravo AF: 0.420

Asia WGS AF: 0.530 AC: 1846 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1023049; hg19: chr20-56139967; COSMIC: COSV60131728; COSMIC: COSV60131728;