20-57561475-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002591.4(PCK1):c.64A>G(p.Ser22Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: PCK1 NM_002591.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.443

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043637663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCK1	NM_002591.4	c.64A>G	p.Ser22Gly	missense_variant	2/10	ENST00000319441.6
PCK1	XM_024451888.2	c.-151A>G		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCK1	ENST00000319441.6	c.64A>G	p.Ser22Gly	missense_variant	2/10	1	NM_002591.4	P1
PCK1	ENST00000467047.1	n.396A>G		non_coding_transcript_exon_variant	1/2	1
PCK1	ENST00000475833.1	n.205A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 251178 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000496 AC: 725 AN: 1461532 Hom.: 0 Cov.: 30 AF XY: 0.000486 AC XY: 353 AN XY: 727050

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000940

Gnomad4 NFE exome AF: 0.000594

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74486

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000519 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.64A>G (p.S22G) alteration is located in exon 2 (coding exon 1) of the PCK1 gene. This alteration results from a A to G substitution at nucleotide position 64, causing the serine (S) at amino acid position 22 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 22 of the PCK1 protein (p.Ser22Gly). This variant is present in population databases (rs140235265, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PCK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 896030). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.035
Sift	Benign	0.080	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.37
MPC		0.086
ClinPred		0.023	T
GERP RS		2.0
Varity_R		0.088
gMVP		0.49

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: rs140235265; hg19: chr20-56136531;