rs369048399

Variant names:

• chr8-28339384-G-C
• rs369048399
• NM_006228.5:c.471G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-28339384-G-C
• chr8-28339384-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

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]

ENSG00000253690 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006228.5. 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
	PNOC	NM_006228.5	MANE Select	c.471G>C	p.Leu157Phe	missense	Exon 3 of 4	NP_006219.1	Q13519-1
	PNOC	NM_001284244.2		c.279G>C	p.Leu93Phe	missense	Exon 2 of 3	NP_001271173.1	Q13519-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNOC	ENST00000301908.8	TSL:1 MANE Select	c.471G>C	p.Leu157Phe	missense	Exon 3 of 4	ENSP00000301908.3	Q13519-1
	PNOC	ENST00000923262.1		c.471G>C	p.Leu157Phe	missense	Exon 3 of 3	ENSP00000593321.1
	PNOC	ENST00000522209.1	TSL:2	c.279G>C	p.Leu93Phe	missense	Exon 2 of 3	ENSP00000430145.1	Q13519-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1427754 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704914

African (AFR) AF: 0.00 AC: 0 AN: 32664

American (AMR) AF: 0.00 AC: 0 AN: 41968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24258

East Asian (EAS) AF: 0.00 AC: 0 AN: 39160

South Asian (SAS) AF: 0.00 AC: 0 AN: 82210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090824

Other (OTH) AF: 0.00 AC: 0 AN: 58762

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	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	D
GERP RS		3.2
Varity_R		0.40
gMVP		0.40
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs369048399; hg19: chr8-28196901;