14-24097052-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004563.4(PCK2):c.190G>A(p.Asp64Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,613,702 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0050 ( 8 hom., cov: 30)

Exomes 𝑓: 0.00065 ( 11 hom. )

Consequence

PCK2
NM_004563.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.51

Variant links:

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]

PCK2 links:

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]

NRL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011896849).

BP6

Variant 14-24097052-G-A is Benign according to our data. Variant chr14-24097052-G-A is described in ClinVar as [Benign]. Clinvar id is 559130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00505 (767/151992) while in subpopulation AFR AF= 0.0173 (715/41424). AF 95% confidence interval is 0.0162. There are 8 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 767 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK2	NM_004563.4 link	c.190G>A	p.Asp64Asn	missense_variant	Exon 2 of 10	ENST00000216780.9	NP_004554.3	Q16822-1A0A384MTT2
NRL	NM_001354768.3 link	c.-27-14177C>T		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 link	c.190G>A	p.Asp64Asn	missense_variant	Exon 2 of 10	1	NM_004563.4	ENSP00000216780.4		Q16822-1
NRL	ENST00000561028.6 link	c.-27-14177C>T		intron_variant	Intron 1 of 2	2	NM_001354768.3	ENSP00000454062.2		P54845-1

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

763

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00146

AC:

366

AN:

251338

Hom.:

AF XY:

0.00113

AC XY:

154

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000648

AC:

947

AN:

1461710

Hom.:

Cov.:

AF XY:

0.000593

AC XY:

431

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0187

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00505

AC:

767

AN:

151992

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

332

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0173

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00594

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00175

AC:

213

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 18, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

PCK2-related disorder

Benign:1

Nov 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

T;T;.

Eigen

Benign

-0.044

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.15

Sift

Benign

0.050

D;D;T

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.16, 0.047

.;B;B

Vest4

0.36

MVP

0.39

MPC

0.059

ClinPred

0.089

GERP RS

3.7

Varity_R

0.16

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over