NM_006228.5:c.375G>C

Variant names:

• chr8-28339288-G-C
• rs200639514
• NM_006228.5:c.375G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006228.5(PNOC):​c.375G>C​(p.Gln125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,611,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: PNOC NM_006228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10418925).

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.375G>C	p.Gln125His	missense	Exon 3 of 4	NP_006219.1	Q13519-1
	PNOC	NM_001284244.2		c.183G>C	p.Gln61His	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.375G>C	p.Gln125His	missense	Exon 3 of 4	ENSP00000301908.3	Q13519-1
	PNOC	ENST00000923262.1		c.375G>C	p.Gln125His	missense	Exon 3 of 3	ENSP00000593321.1
	PNOC	ENST00000518479.5	TSL:4	c.375G>C	p.Gln125His	missense	Exon 3 of 3	ENSP00000428059.1	E7EVP0

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000379 AC: 95 AN: 250494 AF XY: 0.000436

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000880

Gnomad NFE exome AF: 0.000627

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000289 AC: 421 AN: 1458976 Hom.: 1 Cov.: 31 AF XY: 0.000284 AC XY: 206 AN XY: 725126

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.0000224 AC: 1 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86102

European-Finnish (FIN) AF: 0.000918 AC: 49 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000315 AC: 350 AN: 1109692

Other (OTH) AF: 0.000332 AC: 20 AN: 60246

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68054

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000164

EpiControl AF: 0.000356

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	Benign	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.65
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.27
MutPred		0.33		Loss of MoRF binding (P = 0.12)
MVP		0.63
MPC		0.89
ClinPred		0.26	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.21
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200639514; hg19: chr8-28196805;