chr8-28339385-G-A

Position:

• chr8-28339385-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006228.5(PNOC):​c.472G>A​(p.Val158Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNOC NM_006228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37112212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNOC	NM_006228.5	c.472G>A	p.Val158Ile	missense_variant	3/4	ENST00000301908.8	NP_006219.1
PNOC	NM_001284244.2	c.280G>A	p.Val94Ile	missense_variant	2/3		NP_001271173.1
PNOC	XM_005273532.3	c.472G>A	p.Val158Ile	missense_variant	3/4		XP_005273589.1
PNOC	XM_011544559.3	c.472G>A	p.Val158Ile	missense_variant	3/4		XP_011542861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNOC	ENST00000301908.8	c.472G>A	p.Val158Ile	missense_variant	3/4	1	NM_006228.5	ENSP00000301908	P1
PNOC	ENST00000522209.1	c.280G>A	p.Val94Ile	missense_variant	2/3	2		ENSP00000430145
PNOC	ENST00000519592.5	n.487G>A		non_coding_transcript_exon_variant	2/2	2
PNOC	ENST00000518479.5			downstream_gene_variant		4		ENSP00000428059

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.472G>A (p.V158I) alteration is located in exon 3 (coding exon 2) of the PNOC gene. This alteration results from a G to A substitution at nucleotide position 472, causing the valine (V) at amino acid position 158 to be replaced by an isoleucine (I). 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	0.21
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.77	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.28
Sift	Benign	0.043	D;D
Sift4G	Benign	0.068	T;T
Polyphen		0.99	D;.
Vest4		0.24
MutPred		0.42		Loss of catalytic residue at V158 (P = 0.0076);.;
MVP		0.63
MPC		0.41
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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.

Other links and lift over

hg19: chr8-28196902;