chr14-24094411-C-T

Variant names:

• chr14-24094411-C-T
• rs77298044
• NM_004563.4:c.6C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_001291556.2(PCK2):​c.-231C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 1,559,660 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (63 hom., cov: 33)
  • Exomes 𝑓: 0.032 (859 hom.)
• Consequence: PCK2 NM_001291556.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.306
• Publications: 3 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: 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.1).
• BP6: Variant 14-24094411-C-T is Benign according to our data. Variant chr14-24094411-C-T is described in ClinVar as Benign. ClinVar VariationId is 559129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3364/152342) while in subpopulation NFE AF = 0.0363 (2466/68014). AF 95% confidence interval is 0.0351. There are 63 homozygotes in GnomAd4. There are 1540 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK2	NM_004563.4	MANE Select	c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 10	NP_004554.3	A0A384MTT2
	NRL	NM_001354768.3	MANE Select	c.-27-11536G>A		intron	N/A	NP_001341697.1	P54845-1
	PCK2	NM_001291556.2		c.-231C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001278485.1	Q16822-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK2	ENST00000216780.9	TSL:1 MANE Select	c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 10	ENSP00000216780.4	Q16822-1
	PCK2	ENST00000396973.8	TSL:1	c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 7	ENSP00000380171.4	Q16822-2
	NRL	ENST00000561028.6	TSL:2 MANE Select	c.-27-11536G>A		intron	N/A	ENSP00000454062.2	P54845-1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3369 AN: 152224 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0203 AC: 3287 AN: 161820 AF XY: 0.0207

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.00951

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.000343

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0325

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0324 AC: 45530 AN: 1407318 Hom.: 859 Cov.: 31 AF XY: 0.0321 AC XY: 22396 AN XY: 697102

African (AFR) AF: 0.00462 AC: 142 AN: 30710

American (AMR) AF: 0.0113 AC: 436 AN: 38480

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 299 AN: 24912

East Asian (EAS) AF: 0.000140 AC: 5 AN: 35788

South Asian (SAS) AF: 0.0131 AC: 1058 AN: 80624

European-Finnish (FIN) AF: 0.0236 AC: 1035 AN: 43814

Middle Eastern (MID) AF: 0.0169 AC: 92 AN: 5440

European-Non Finnish (NFE) AF: 0.0376 AC: 40950 AN: 1089164

Other (OTH) AF: 0.0259 AC: 1513 AN: 58386

GnomAD4 genome AF: 0.0221 AC: 3364 AN: 152342 Hom.: 63 Cov.: 33 AF XY: 0.0207 AC XY: 1540 AN XY: 74488

African (AFR) AF: 0.00637 AC: 265 AN: 41592

American (AMR) AF: 0.0146 AC: 224 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4832

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0363 AC: 2466 AN: 68014

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0298 Hom.: 37

Bravo AF: 0.0210

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		0.31
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77298044; hg19: chr14-24563620; COSMIC: COSV53747891; COSMIC: COSV53747891;