Genetic Variant OPRK1:p.Gln213Leu (chr8-53229802-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000912.5(OPRK1):c.638A>T(p.Gln213Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,278 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q213R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

OPRK1
NM_000912.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

Publications

0 publications found

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:

LOC105375836 (HGNC:):

LOC105375836 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRK1	NM_000912.5 link	c.638A>T	p.Gln213Leu	missense_variant	Exon 4 of 4	ENST00000265572.8	NP_000903.2	P41145-1
OPRK1	NM_001318497.2 link	c.638A>T	p.Gln213Leu	missense_variant	Exon 4 of 4		NP_001305426.1	P41145A0A5F9ZI09
OPRK1	NM_001282904.2 link	c.371A>T	p.Gln124Leu	missense_variant	Exon 5 of 5		NP_001269833.1	P41145-2
LOC105375836	NR_188096.1 link	n.2514T>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRK1	ENST00000265572.8 link	c.638A>T	p.Gln213Leu	missense_variant	Exon 4 of 4	1	NM_000912.5	ENSP00000265572.3		P41145-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431278

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32134

American (AMR)

AF:

0.00

AC:

AN:

39860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24336

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

81862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1096654

Other (OTH)

AF:

0.00

AC:

AN:

58782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.33

.;.;T;.;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;.;.;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.58

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.27

.;.;N;.;N

PhyloP100

8.0

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.9

.;.;D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.49

.;.;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T

Polyphen

0.025

.;.;B;.;B

Vest4

0.76

MutPred

0.43

.;.;Gain of glycosylation at S211 (P = 0.0853);.;Gain of glycosylation at S211 (P = 0.0853);

MVP

0.53

MPC

0.98

ClinPred

0.81

GERP RS

4.5

Varity_R

0.51

gMVP

0.79

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.68

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.68

Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr8-53229802-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over