rs1042531

Variant names:

• chr20-57565924-T-G
• rs1042531
• NM_002591.4:c.*120T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002591.4(PCK1):​c.*120T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 688,420 control chromosomes in the GnomAD database, including 53,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16795 hom., cov: 31)
  • Exomes 𝑓: 0.36 (36401 hom.)
• Consequence: PCK1 NM_002591.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.03

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-57565924-T-G is Benign according to our data. Variant chr20-57565924-T-G is described in ClinVar as [Benign]. Clinvar id is 338898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK1	NM_002591.4	c.*120T>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000319441.6	NP_002582.3
PCK1	XM_024451888.2	c.*120T>G		3_prime_UTR_variant	Exon 9 of 9		XP_024307656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCK1	ENST00000319441.6	c.*120T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_002591.4	ENSP00000319814.4
PCK1	ENST00000467047.1	n.4631T>G		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67269 AN: 151852 Hom.: 16777 Cov.: 31

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.359 AC: 192682 AN: 536450 Hom.: 36401 Cov.: 7 AF XY: 0.356 AC XY: 98722 AN XY: 277536

Gnomad4 AFR exome AF: 0.688

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.380

GnomAD4 genome AF: 0.443 AC: 67327 AN: 151970 Hom.: 16795 Cov.: 31 AF XY: 0.436 AC XY: 32356 AN XY: 74280

Gnomad4 AFR AF: 0.684

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.433

Alfa AF: 0.388 Hom.: 11671

Bravo AF: 0.452

Asia WGS AF: 0.289 AC: 1004 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.095
DANN	Benign	0.55

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: rs1042531; hg19: chr20-56140980; COSMIC: COSV60127701; COSMIC: COSV60127701;