Variant chr8-28339384-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006228.5(PNOC):c.471G>C(p.Leu157Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,427,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PNOC
NM_006228.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

PNOC (HGNC:9163): (prepronociceptin) This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include nociceptin, nocistatin, and orphanin FQ2 (OFQ2). Nociceptin, also known as orphanin FQ, is a 17-amino acid neuropeptide that binds to the nociceptin receptor to induce increased pain sensitivity, and may additionally regulate body temperature, learning and memory, and hunger. Another product of the encoded preproprotein, nocistatin, may inhibit the effects of nociceptin. [provided by RefSeq, Jul 2015]

PNOC links:

PNOC (HGNC:):

PNOC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNOC	NM_006228.5 linkuse as main transcript	c.471G>C	p.Leu157Phe	missense_variant	3/4	ENST00000301908.8	NP_006219.1	Q13519-1
PNOC	NM_001284244.2 linkuse as main transcript	c.279G>C	p.Leu93Phe	missense_variant	2/3		NP_001271173.1	Q13519-2
PNOC	XM_005273532.3 linkuse as main transcript	c.471G>C	p.Leu157Phe	missense_variant	3/4		XP_005273589.1
PNOC	XM_011544559.3 linkuse as main transcript	c.471G>C	p.Leu157Phe	missense_variant	3/4		XP_011542861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PNOC	ENST00000301908.8 linkuse as main transcript	c.471G>C	p.Leu157Phe	missense_variant	3/4	1	NM_006228.5	ENSP00000301908.3	Q13519-1
PNOC	ENST00000522209.1 linkuse as main transcript	c.279G>C	p.Leu93Phe	missense_variant	2/3	2		ENSP00000430145.1	Q13519-2
PNOC	ENST00000519592.5 linkuse as main transcript	n.486G>C		non_coding_transcript_exon_variant	2/2	2
PNOC	ENST00000518479.5 linkuse as main transcript	c.*8G>C		downstream_gene_variant		4		ENSP00000428059.1	E7EVP0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1427754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.471G>C (p.L157F) alteration is located in exon 3 (coding exon 2) of the PNOC gene. This alteration results from a G to C substitution at nucleotide position 471, causing the leucine (L) at amino acid position 157 to be replaced by a phenylalanine (F). 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

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.41

Loss of phosphorylation at Y156 (P = 0.2965);.;

MVP

0.74

MPC

0.84

ClinPred

0.97

GERP RS

3.2

Varity_R

0.40

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over