20-57562984-G-C

Variant names:

• chr20-57562984-G-C
• rs2070755
• ENST00000467047.1:n.1905G>C

Variant summary

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

The ENST00000467047.1(PCK1):​n.1905G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,587,932 control chromosomes in the GnomAD database, including 192,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16952 hom., cov: 34)
  • Exomes 𝑓: 0.49 (175100 hom.)
• Consequence: PCK1 ENST00000467047.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.543
• Publications: 12 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=-0.87).
• BP6: Variant 20-57562984-G-C is Benign according to our data. Variant chr20-57562984-G-C is described in ClinVar as Benign. ClinVar VariationId is 1234699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK1	NM_002591.4	c.611-44G>C		intron_variant	Intron 4 of 9	ENST00000319441.6	NP_002582.3
PCK1	XM_024451888.2	c.215-44G>C		intron_variant	Intron 3 of 8		XP_024307656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCK1	ENST00000467047.1	n.1905G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
PCK1	ENST00000319441.6	c.611-44G>C		intron_variant	Intron 4 of 9	1	NM_002591.4	ENSP00000319814.4
PCK1	ENST00000470051.1	n.151G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
PCK1	ENST00000498194.1	n.553-44G>C		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.467 AC: 71038 AN: 152082 Hom.: 16943 Cov.: 34

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.495

GnomAD2 exomes AF: 0.469 AC: 114321 AN: 243830 AF XY: 0.468

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.512

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.498

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.491 AC: 705214 AN: 1435732 Hom.: 175100 Cov.: 29 AF XY: 0.489 AC XY: 348376 AN XY: 712504

African (AFR) AF: 0.400 AC: 13145 AN: 32832

American (AMR) AF: 0.514 AC: 22595 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 12903 AN: 25376

East Asian (EAS) AF: 0.337 AC: 13288 AN: 39396

South Asian (SAS) AF: 0.408 AC: 34619 AN: 84800

European-Finnish (FIN) AF: 0.504 AC: 26539 AN: 52688

Middle Eastern (MID) AF: 0.598 AC: 3393 AN: 5674

European-Non Finnish (NFE) AF: 0.503 AC: 549704 AN: 1091814

Other (OTH) AF: 0.490 AC: 29028 AN: 59232

GnomAD4 genome AF: 0.467 AC: 71071 AN: 152200 Hom.: 16952 Cov.: 34 AF XY: 0.467 AC XY: 34734 AN XY: 74420

African (AFR) AF: 0.402 AC: 16699 AN: 41508

American (AMR) AF: 0.522 AC: 7996 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1765 AN: 3472

East Asian (EAS) AF: 0.324 AC: 1671 AN: 5164

South Asian (SAS) AF: 0.416 AC: 2012 AN: 4834

European-Finnish (FIN) AF: 0.510 AC: 5401 AN: 10592

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33797 AN: 68008

Other (OTH) AF: 0.498 AC: 1052 AN: 2114

Alfa AF: 0.478 Hom.: 3206

Bravo AF: 0.466

Asia WGS AF: 0.381 AC: 1325 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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.58
DANN	Benign	0.41
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2070755; hg19: chr20-56138040; COSMIC: COSV60126011; COSMIC: COSV60126011;