Genetic Variant PCK2:p.Arg25Leu (chr14-24096936-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004563.4(PCK2):c.74G>T(p.Arg25Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Consequence

PCK2
NM_004563.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.33

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

retinitis pigmentosa 27
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
enhanced S-cone syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NRL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004563.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCK2	NM_004563.4	MANE Select	c.74G>T	p.Arg25Leu	missense	Exon 2 of 10	NP_004554.3	A0A384MTT2
NRL	NM_001354768.3	MANE Select	c.-27-14061C>A		intron	N/A	NP_001341697.1	P54845-1
PCK2	NM_001018073.3		c.74G>T	p.Arg25Leu	missense	Exon 2 of 7	NP_001018083.2	Q16822-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCK2	ENST00000216780.9	TSL:1 MANE Select	c.74G>T	p.Arg25Leu	missense	Exon 2 of 10	ENSP00000216780.4	Q16822-1
PCK2	ENST00000396973.8	TSL:1	c.74G>T	p.Arg25Leu	missense	Exon 2 of 7	ENSP00000380171.4	Q16822-2
NRL	ENST00000561028.6	TSL:2 MANE Select	c.-27-14061C>A		intron	N/A	ENSP00000454062.2	P54845-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0087

Eigen

Benign

-0.083

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.83

M_CAP

Benign

0.0052

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

PhyloP100

5.3

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.24

REVEL

Benign

0.040

Sift

Uncertain

0.010

Sift4G

Uncertain

0.012

Polyphen

0.013

Vest4

0.63

MutPred

0.37

Loss of helix (P = 0.0104)

MVP

0.53

MPC

0.088

ClinPred

0.68

GERP RS

5.5

Varity_R

0.18

gMVP

0.72

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over