NM_004563.4:c.68C>G

Variant names:

• chr14-24096930-C-G
• rs61752842
• NM_004563.4:c.68C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_004563.4(PCK2):​c.68C>G​(p.Ser23*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,536 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0031 (8 hom.)
• Consequence: PCK2 NM_004563.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:2
• Conservation: PhyloP100: 0.769

Genes affected

PCK2 (HGNC:8725): (phosphoenolpyruvate carboxykinase 2, mitochondrial) This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2014]

NRL (HGNC:8002): (neural retina leucine zipper) This gene encodes a basic motif-leucine zipper transcription factor of the Maf subfamily. The encoded protein is conserved among vertebrates and is a critical intrinsic regulator of photoceptor development and function. Mutations in this gene have been associated with retinitis pigmentosa and retinal degenerative diseases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.965 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK2	NM_004563.4	c.68C>G	p.Ser23*	stop_gained	Exon 2 of 10	ENST00000216780.9	NP_004554.3
NRL	NM_001354768.3	c.-27-14055G>C		intron_variant	Intron 1 of 2	ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCK2	ENST00000216780.9	c.68C>G	p.Ser23*	stop_gained	Exon 2 of 10	1	NM_004563.4	ENSP00000216780.4
NRL	ENST00000561028.6	c.-27-14055G>C		intron_variant	Intron 1 of 2	2	NM_001354768.3	ENSP00000454062.2

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152174 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00188 AC: 472 AN: 250952 Hom.: 1 AF XY: 0.00179 AC XY: 243 AN XY: 135654

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00310 AC: 4526 AN: 1461244 Hom.: 8 Cov.: 31 AF XY: 0.00303 AC XY: 2203 AN XY: 726976

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152292 Hom.: 2 Cov.: 30 AF XY: 0.00180 AC XY: 134 AN XY: 74464

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00300 Hom.: 0

Bravo AF: 0.00204

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00197 AC: 239

EpiCase AF: 0.00333

EpiControl AF: 0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4 Benign:1

Jan 10, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with ataxia and weakness exacerbated by illness who also harbors an an additional missense variant in the PCK2 gene (PMID: 36845668); Reported as a de novo variant in a patient from the Deciphering Developmental Disorders cohort who also harbors additional de novo variants in a large cohort of individuals with cardiovascular disease traits (PMID: 31345219, 31785789); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 31345219, 36845668, 31785789) -

Nov 20, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 30, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser23X variant in PCK2 has not been previously reported in individuals wit h PEPCK deficiency, but has been identified in 0.5% (61/11556) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61752842) including two homozygote individuals. This nonsense variant le ads to a premature termination codon at position 23, which is predicted to lead to a truncated or absent protein. However, a role for PCK2 loss of function vari ants in disease has not been established. In summary, while the clinical signifi cance of the p.Ser23X variant is uncertain, the frequency data in ExAC suggest a more likely benign role. -

Phosphoenolpyruvate carboxykinase deficiency, mitochondrial Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.50	D
Vest4		0.75
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs61752842; hg19: chr14-24566139;