8-28339218-G-T

Variant names:

• chr8-28339218-G-T
• NM_006228.5:c.305G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006228.5(PNOC):​c.305G>T​(p.Arg102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PNOC NM_006228.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32357588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNOC	NM_006228.5	c.305G>T	p.Arg102Leu	missense_variant	Exon 3 of 4	ENST00000301908.8	NP_006219.1
PNOC	NM_001284244.2	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 3		NP_001271173.1
PNOC	XM_005273532.3	c.305G>T	p.Arg102Leu	missense_variant	Exon 3 of 4		XP_005273589.1
PNOC	XM_011544559.3	c.305G>T	p.Arg102Leu	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.305G>T	p.Arg102Leu	missense_variant	Exon 3 of 4	1	NM_006228.5	ENSP00000301908.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460178 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;D;.
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.0	.;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.20
Sift	Benign	0.061	T;T;D
Sift4G	Benign	0.092	T;T;D
Polyphen		0.98	.;D;.
Vest4		0.45, 0.31
MutPred		0.40		Loss of MoRF binding (P = 0.056);Loss of MoRF binding (P = 0.056);.;
MVP		0.69
MPC		0.64
ClinPred		0.56	D
GERP RS		1.0
Varity_R		0.071
gMVP		0.42

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: chr8-28196735; COSMIC: COSV100108428;