rs6070157

Variant names:

• chr20-57562128-C-T
• rs6070157
• NM_002591.4:c.282C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002591.4(PCK1):​c.282C>T​(p.Ile94Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,658 control chromosomes in the GnomAD database, including 30,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2424 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28131 hom.)
• Consequence: PCK1 NM_002591.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.472
• Publications: 26 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-57562128-C-T is Benign according to our data. Variant chr20-57562128-C-T is described in ClinVar as Benign. ClinVar VariationId is 338874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 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.282C>T	p.Ile94Ile	synonymous	Exon 3 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.282C>T	p.Ile94Ile	synonymous	Exon 3 of 10	ENSP00000319814.4	P35558-1
	PCK1	ENST00000467047.1	TSL:1	n.1049C>T		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.282C>T	p.Ile94Ile	synonymous	Exon 2 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26059 AN: 152038 Hom.: 2416 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.172 AC: 43260 AN: 251326 AF XY: 0.176

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.00794

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.191 AC: 279285 AN: 1461502 Hom.: 28131 Cov.: 33 AF XY: 0.192 AC XY: 139361 AN XY: 727064

African (AFR) AF: 0.126 AC: 4221 AN: 33478

American (AMR) AF: 0.129 AC: 5775 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4531 AN: 26136

East Asian (EAS) AF: 0.00509 AC: 202 AN: 39700

South Asian (SAS) AF: 0.171 AC: 14770 AN: 86250

European-Finnish (FIN) AF: 0.223 AC: 11936 AN: 53414

Middle Eastern (MID) AF: 0.153 AC: 884 AN: 5768

European-Non Finnish (NFE) AF: 0.204 AC: 226495 AN: 1111656

Other (OTH) AF: 0.173 AC: 10471 AN: 60382

GnomAD4 genome AF: 0.172 AC: 26099 AN: 152156 Hom.: 2424 Cov.: 33 AF XY: 0.170 AC XY: 12649 AN XY: 74386

African (AFR) AF: 0.130 AC: 5388 AN: 41498

American (AMR) AF: 0.144 AC: 2195 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3468

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5186

South Asian (SAS) AF: 0.154 AC: 746 AN: 4830

European-Finnish (FIN) AF: 0.219 AC: 2317 AN: 10580

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14213 AN: 67986

Other (OTH) AF: 0.156 AC: 330 AN: 2112

Alfa AF: 0.191 Hom.: 9502

Bravo AF: 0.160

Asia WGS AF: 0.0800 AC: 281 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.199

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Phosphoenolpyruvate carboxykinase deficiency, cytosolic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6070157; hg19: chr20-56137184; COSMIC: COSV108117465; COSMIC: COSV108117465;