14-24094422-G-A

Variant names:

• chr14-24094422-G-A
• rs1490263802
• NM_004563.4:c.17G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_004563.4(PCK2):​c.17G>A​(p.Arg6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,404,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PCK2 NM_004563.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19872108).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK2	NM_004563.4	c.17G>A	p.Arg6His	missense_variant	Exon 1 of 10	ENST00000216780.9	NP_004554.3
NRL	NM_001354768.3	c.-27-11547C>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	c.17G>A	p.Arg6His	missense_variant	Exon 1 of 10	1	NM_004563.4	ENSP00000216780.4
NRL	ENST00000561028.6	c.-27-11547C>T		intron_variant	Intron 1 of 2	2	NM_001354768.3	ENSP00000454062.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1404314 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 695512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17G>A (p.R6H) alteration is located in exon 1 (coding exon 1) of the PCK2 gene. This alteration results from a G to A substitution at nucleotide position 17, causing the arginine (R) at amino acid position 6 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	0.079
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.077
Sift	Benign	0.075	T;D
Sift4G	Uncertain	0.059	T;D
Polyphen		0.91	P;D
Vest4		0.29
MutPred		0.34		Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);
MVP		0.56
MPC		0.095
ClinPred		0.80	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.070
gMVP		0.63

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: rs1490263802; hg19: chr14-24563631;