chr8-53250967-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000912.5(OPRK1):c.71C>G(p.Pro24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,606,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 1 hom. )

Consequence

OPRK1
NM_000912.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

Variant links:

Genes affected

OPRK1 (HGNC:8154): (opioid receptor kappa 1) This gene encodes an opioid receptor, which is a member of the 7 transmembrane-spanning G protein-coupled receptor family. It functions as a receptor for endogenous ligands, as well as a receptor for various synthetic opioids. Ligand binding results in inhibition of adenylate cyclase activity and neurotransmitter release. This opioid receptor plays a role in the perception of pain and mediating the hypolocomotor, analgesic and aversive actions of synthetic opioids. Variations in this gene have also been associated with alcohol dependence and opiate addiction. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

OPRK1 links:

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ACMG classification

Classification made for transcript

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=0.104914874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRK1	NM_000912.5 link	c.71C>G	p.Pro24Arg	missense_variant	Exon 2 of 4	ENST00000265572.8	NP_000903.2	P41145-1
OPRK1	NM_001318497.2 link	c.71C>G	p.Pro24Arg	missense_variant	Exon 2 of 4		NP_001305426.1	P41145A0A5F9ZI09
OPRK1	NM_001282904.2 link	c.-371C>G		5_prime_UTR_variant	Exon 2 of 5		NP_001269833.1	P41145-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OPRK1	ENST00000265572.8 link	c.71C>G	p.Pro24Arg	missense_variant	Exon 2 of 4	1	NM_000912.5	ENSP00000265572.3	P41145-1
OPRK1	ENST00000520287.5 link	c.71C>G	p.Pro24Arg	missense_variant	Exon 1 of 3	1		ENSP00000429706.1	P41145-1
OPRK1	ENST00000522508.1 link	n.71C>G		non_coding_transcript_exon_variant	Exon 2 of 5	1		ENSP00000428231.1	E5RJI5
OPRK1	ENST00000673285.2 link	c.71C>G	p.Pro24Arg	missense_variant	Exon 2 of 4			ENSP00000500765.2	A0A5F9ZI09

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000101

AC:

AN:

227052

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

124930

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000230

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000504

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000542

GnomAD4 exome

AF:

0.0000461

AC:

AN:

1454612

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

722978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000903

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.0000467

Gnomad4 FIN exome

AF:

0.000116

Gnomad4 NFE exome

AF:

0.0000352

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000112

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000679

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000126

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71C>G (p.P24R) alteration is located in exon 2 (coding exon 1) of the OPRK1 gene. This alteration results from a C to G substitution at nucleotide position 71, causing the proline (P) at amino acid position 24 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

0.079

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.46

T;.;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.8

.;L;L

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.61

.;N;N

REVEL

Benign

0.11

Sift

Benign

0.14

.;T;T

Sift4G

Benign

0.062

T;T;T

Polyphen

0.0030

.;B;B

Vest4

0.36

MutPred

0.24

Loss of catalytic residue at P23 (P = 0.016);Loss of catalytic residue at P23 (P = 0.016);Loss of catalytic residue at P23 (P = 0.016);

MVP

0.83

MPC

0.31

ClinPred

0.034

GERP RS

3.1

Varity_R

0.062

gMVP

0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over