14-24096936-G-T

Variant names:

• chr14-24096936-G-T
• rs777117778
• NM_004563.4:c.74G>T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PCK2 NM_004563.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK2	NM_004563.4	c.74G>T	p.Arg25Leu	missense_variant	Exon 2 of 10	ENST00000216780.9	NP_004554.3
NRL	NM_001354768.3	c.-27-14061C>A		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.74G>T	p.Arg25Leu	missense_variant	Exon 2 of 10	1	NM_004563.4	ENSP00000216780.4
NRL	ENST00000561028.6	c.-27-14061C>A		intron_variant	Intron 1 of 2	2	NM_001354768.3	ENSP00000454062.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0087	T;T;.
Eigen	Benign	-0.083
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0052	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	.;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.012	D;T;D
Polyphen		0.013, 0.0010	.;B;B
Vest4		0.63
MutPred		0.37		.;Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.53
MPC		0.088
ClinPred		0.68	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.72

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: rs777117778; hg19: chr14-24566145;