rs1042521

Variant names:

• chr20-57561480-A-G
• rs1042521
• NM_002591.4:c.69A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-57561480-A-G
• chr20-57561480-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002591.4(PCK1):​c.69A>G​(p.Leu23Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,612,858 control chromosomes in the GnomAD database, including 191,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15133 hom., cov: 33)
  • Exomes 𝑓: 0.49 (176244 hom.)
• Consequence: PCK1 NM_002591.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 20-57561480-A-G is Benign according to our data. Variant chr20-57561480-A-G is described in ClinVar as Benign. ClinVar VariationId is 338868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	NM_002591.4	MANE Select	c.69A>G	p.Leu23Leu	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.69A>G	p.Leu23Leu	synonymous	Exon 2 of 10	ENSP00000319814.4	P35558-1
	PCK1	ENST00000467047.1	TSL:1	n.401A>G		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.69A>G	p.Leu23Leu	synonymous	Exon 1 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66747 AN: 151936 Hom.: 15144 Cov.: 33

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.450 AC: 112932 AN: 251010 AF XY: 0.457

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.503

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.487 AC: 712023 AN: 1460804 Hom.: 176244 Cov.: 38 AF XY: 0.487 AC XY: 353808 AN XY: 726732

African (AFR) AF: 0.337 AC: 11281 AN: 33472

American (AMR) AF: 0.337 AC: 15084 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12573 AN: 26136

East Asian (EAS) AF: 0.350 AC: 13908 AN: 39694

South Asian (SAS) AF: 0.450 AC: 38762 AN: 86232

European-Finnish (FIN) AF: 0.481 AC: 25576 AN: 53132

Middle Eastern (MID) AF: 0.576 AC: 3323 AN: 5768

European-Non Finnish (NFE) AF: 0.506 AC: 562292 AN: 1111298

Other (OTH) AF: 0.484 AC: 29224 AN: 60352

GnomAD4 genome AF: 0.439 AC: 66732 AN: 152054 Hom.: 15133 Cov.: 33 AF XY: 0.435 AC XY: 32370 AN XY: 74334

African (AFR) AF: 0.340 AC: 14094 AN: 41462

American (AMR) AF: 0.403 AC: 6162 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1660 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1924 AN: 5158

South Asian (SAS) AF: 0.443 AC: 2136 AN: 4826

European-Finnish (FIN) AF: 0.482 AC: 5098 AN: 10570

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 34008 AN: 67954

Other (OTH) AF: 0.459 AC: 969 AN: 2112

Alfa AF: 0.474 Hom.: 11251

Bravo AF: 0.429

Asia WGS AF: 0.392 AC: 1366 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Phosphoenolpyruvate carboxykinase deficiency, cytosolic (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.4
DANN	Benign	0.63
PhyloP100		1.8
PromoterAI		0.069	Neutral
Mutation Taster		=284/16	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: rs1042521; hg19: chr20-56136536; COSMIC: COSV60126620; COSMIC: COSV60126620;