8-28339078-C-A

Position:

• chr8-28339078-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006228.5(PNOC):​c.165C>A​(p.Ser55Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: -0.120

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 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=0.15703699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNOC	NM_006228.5	c.165C>A	p.Ser55Arg	missense_variant	3/4	ENST00000301908.8	NP_006219.1
PNOC	XM_005273532.3	c.165C>A	p.Ser55Arg	missense_variant	3/4		XP_005273589.1
PNOC	XM_011544559.3	c.165C>A	p.Ser55Arg	missense_variant	3/4		XP_011542861.1
PNOC	NM_001284244.2	c.-28C>A		5_prime_UTR_variant	2/3		NP_001271173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNOC	ENST00000301908.8	c.165C>A	p.Ser55Arg	missense_variant	3/4	1	NM_006228.5	ENSP00000301908	P1
	ENST00000521731.1	n.178G>T		non_coding_transcript_exon_variant	1/2	2

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

Dec 01, 2022

The c.165C>A (p.S55R) alteration is located in exon 3 (coding exon 2) of the PNOC gene. This alteration results from a C to A substitution at nucleotide position 165, causing the serine (S) at amino acid position 55 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	0.51	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.020	.;B
Vest4		0.21
MutPred		0.54		Gain of MoRF binding (P = 0.0477);Gain of MoRF binding (P = 0.0477);
MVP		0.31
MPC		0.75
ClinPred		0.74	D
GERP RS		4.0
Varity_R		0.10
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-28196595;