rs2759407

Variant names:

• chr14-24100738-T-C
• rs2759407
• NM_004563.4:c.1234+525T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004563.4(PCK2):​c.1234+525T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 152,240 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.072 (507 hom., cov: 32)
• Consequence: PCK2 NM_004563.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.180
• Publications: 4 publications found

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]

NRL Gene-Disease associations (from GenCC):

• retinitis pigmentosa 27

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• enhanced S-cone syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK2	NM_004563.4	c.1234+525T>C		intron_variant	Intron 7 of 9	ENST00000216780.9	NP_004554.3
NRL	NM_001354768.3	c.-28+13984A>G		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.1234+525T>C		intron_variant	Intron 7 of 9	1	NM_004563.4	ENSP00000216780.4
NRL	ENST00000561028.6	c.-28+13984A>G		intron_variant	Intron 1 of 2	2	NM_001354768.3	ENSP00000454062.2

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10929 AN: 152122 Hom.: 507 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0908

Gnomad OTH AF: 0.0756

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0718 AC: 10929 AN: 152240 Hom.: 507 Cov.: 32 AF XY: 0.0745 AC XY: 5543 AN XY: 74424

African (AFR) AF: 0.0355 AC: 1474 AN: 41550

American (AMR) AF: 0.0629 AC: 963 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3466

East Asian (EAS) AF: 0.0288 AC: 149 AN: 5174

South Asian (SAS) AF: 0.0690 AC: 333 AN: 4826

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10586

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0907 AC: 6172 AN: 68022

Other (OTH) AF: 0.0748 AC: 158 AN: 2112

Alfa AF: 0.0779 Hom.: 627

Bravo AF: 0.0619

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.0
DANN	Benign	0.83
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2759407; hg19: chr14-24569947;