rs61752842

Positions:

• chr14-24096930-C-G
• chr14-24096930-C-T

Variant summary

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

The ENST00000216780.9(PCK2):​c.68C>G​(p.Ser23Ter) 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 ENST00000216780.9 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 2 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCK2	NM_004563.4	c.68C>G	p.Ser23Ter	stop_gained	2/10	ENST00000216780.9	NP_004554.3
NRL	NM_001354768.3	c.-27-14055G>C		intron_variant		ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCK2	ENST00000216780.9	c.68C>G	p.Ser23Ter	stop_gained	2/10	1	NM_004563.4	ENSP00000216780	P1
NRL	ENST00000561028.6	c.-27-14055G>C		intron_variant		2	NM_001354768.3	ENSP00000454062	P1

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

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2016

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

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

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
MutationTaster	Benign	1.0	N;A;A;A;N;N;N
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;