chr8-28339288-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10418925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNOC	NM_006228.5	c.375G>C	p.Gln125His	missense_variant	Exon 3 of 4	ENST00000301908.8	NP_006219.1
PNOC	NM_001284244.2	c.183G>C	p.Gln61His	missense_variant	Exon 2 of 3		NP_001271173.1
PNOC	XM_005273532.3	c.375G>C	p.Gln125His	missense_variant	Exon 3 of 4		XP_005273589.1
PNOC	XM_011544559.3	c.375G>C	p.Gln125His	missense_variant	Exon 3 of 4		XP_011542861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNOC	ENST00000301908.8	c.375G>C	p.Gln125His	missense_variant	Exon 3 of 4	1	NM_006228.5	ENSP00000301908.3

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

GnomAD3 exomes AF: 0.000379 AC: 95 AN: 250494 Hom.: 1 AF XY: 0.000436 AC XY: 59 AN XY: 135392

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 SAS 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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.000332

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.375G>C (p.Q125H) alteration is located in exon 3 (coding exon 2) of the PNOC gene. This alteration results from a G to C substitution at nucleotide position 375, causing the glutamine (Q) at amino acid position 125 to be replaced by a histidine (H). 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	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.23	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.27, 0.28
MutPred		0.33		Loss of MoRF binding (P = 0.12);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs200639514; hg19: chr8-28196805;