chr8-28339266-C-G

Variant names:

• chr8-28339266-C-G
• rs76786693
• NM_006228.5:c.353C>G

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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
• Publications: 7 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: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNOC	NM_006228.5	MANE Select	c.353C>G	p.Ala118Gly	missense	Exon 3 of 4	NP_006219.1
	PNOC	NM_001284244.2		c.161C>G	p.Ala54Gly	missense	Exon 2 of 3	NP_001271173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNOC	ENST00000301908.8	TSL:1 MANE Select	c.353C>G	p.Ala118Gly	missense	Exon 3 of 4	ENSP00000301908.3
	PNOC	ENST00000518479.5	TSL:4	c.353C>G	p.Ala118Gly	missense	Exon 3 of 3	ENSP00000428059.1
	PNOC	ENST00000522209.1	TSL:2	c.161C>G	p.Ala54Gly	missense	Exon 2 of 3	ENSP00000430145.1

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

GnomAD2 exomes AF: 0.0214 AC: 5367 AN: 250598 AF XY: 0.0245

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 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

African (AFR) AF: 0.000479 AC: 16 AN: 33382

American (AMR) AF: 0.000314 AC: 14 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26096

East Asian (EAS) AF: 0.152 AC: 6017 AN: 39520

South Asian (SAS) AF: 0.0884 AC: 7606 AN: 86080

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53374

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5754

European-Non Finnish (NFE) AF: 0.000153 AC: 169 AN: 1107188

Other (OTH) AF: 0.0120 AC: 724 AN: 60124

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

African (AFR) AF: 0.000433 AC: 18 AN: 41564

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.131 AC: 677 AN: 5178

South Asian (SAS) AF: 0.0960 AC: 463 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

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 v4.9

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
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.066
Sift	Benign	0.11	T
Sift4G	Benign	0.43	T
Polyphen		0.022	B
Vest4		0.060
MPC		0.28
ClinPred		0.0082	T
GERP RS		2.9
Varity_R		0.064
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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