Genetic Variant PNOC:c.-23-4897C>T (chr8-28324238-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_006228.5(PNOC):c.-23-4897C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 152,270 control chromosomes in the GnomAD database, including 123 homozygotes. 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: 𝑓 0.032 ( 123 hom., cov: 32)

Consequence

PNOC
NM_006228.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.146

Publications

4 publications found

Variant links:

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]

PNOC links:

ENSG00000253690 (HGNC:):

ENSG00000253690 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0324 (4934/152270) while in subpopulation NFE AF = 0.048 (3268/68020). AF 95% confidence interval is 0.0467. There are 123 homozygotes in GnomAd4. There are 2428 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 123 AR gene

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.-23-4897C>T		intron	N/A	NP_006219.1	Q13519-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PNOC	ENST00000301908.8	TSL:1 MANE Select	c.-23-4897C>T	intron	N/A	ENSP00000301908.3	Q13519-1
PNOC	ENST00000923262.1		c.-23-4897C>T	intron	N/A	ENSP00000593321.1
PNOC	ENST00000518479.5	TSL:4	c.-23-4897C>T	intron	N/A	ENSP00000428059.1	E7EVP0

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4937

AN:

152152

Hom.:

123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00758

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0361

Gnomad FIN

AF:

0.0587

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0481

Gnomad OTH

AF:

0.0263

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0324

AC:

4934

AN:

152270

Hom.:

123

Cov.:

AF XY:

0.0326

AC XY:

2428

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00756

AC:

314

AN:

41558

American (AMR)

AF:

0.0208

AC:

319

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0386

AC:

134

AN:

3468

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.0357

AC:

172

AN:

4814

European-Finnish (FIN)

AF:

0.0587

AC:

622

AN:

10604

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0480

AC:

3268

AN:

68020

Other (OTH)

AF:

0.0260

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

249

498

747

996

1245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0410

Hom.:

342

Bravo

AF:

0.0281

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.2

(source)

DANN

Benign

0.43

PhyloP100

0.15

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over