rs76786693

chr8-28339266-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006228.5(PNOC):c.353C>G(p.Ala118Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0098 in 1,608,402 control chromosomes in the GnomAD database, including 1,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0078 (62 hom., cov: 32)
  • Exomes 𝑓: 0.010 (966 hom.)
• Consequence: PNOC NM_006228.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017537773).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNOC	NM_006228.5	c.353C>G	p.Ala118Gly	missense_variant	3/4	ENST00000301908.8
PNOC	NM_001284244.2	c.161C>G	p.Ala54Gly	missense_variant	2/3
PNOC	XM_005273532.3	c.353C>G	p.Ala118Gly	missense_variant	3/4
PNOC	XM_011544559.3	c.353C>G	p.Ala118Gly	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNOC	ENST00000301908.8	c.353C>G	p.Ala118Gly	missense_variant	3/4	1	NM_006228.5	P1
	ENST00000521731.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00783 AC: 1191 AN: 152172 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0953

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.0214 AC: 5367 AN: 250598 Hom.: 312 AF XY: 0.0245 AC XY: 3325 AN XY: 135462

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0993

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0100 AC: 14576 AN: 1456110 Hom.: 966 Cov.: 31 AF XY: 0.0122 AC XY: 8814 AN XY: 722988

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.0884

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00783 AC: 1193 AN: 152292 Hom.: 62 Cov.: 32 AF XY: 0.0102 AC XY: 756 AN XY: 74470

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0960

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.00570

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0226 AC: 2738

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	14
Dann	Benign	0.89
DEOGEN2	Benign	0.046	T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.96	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.066
Sift	Benign	0.11	T;T;D
Sift4G	Benign	0.43	T;T;T
Polyphen		0.022	.;B;.
Vest4		0.060, 0.20
MPC		0.28
ClinPred		0.0082	T
GERP RS		2.9
Varity_R		0.064
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs76786693; hg19: chr8-28196783; COSMIC: COSV57283087; COSMIC: COSV57283087;