8-53229802-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000912.5(OPRK1):​c.638A>G​(p.Gln213Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000632 in 1,583,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

OPRK1
NM_000912.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OPRK1NM_000912.5 linkc.638A>G p.Gln213Arg missense_variant Exon 4 of 4 ENST00000265572.8 NP_000903.2 P41145-1
OPRK1NM_001318497.2 linkc.638A>G p.Gln213Arg missense_variant Exon 4 of 4 NP_001305426.1 P41145A0A5F9ZI09
OPRK1NM_001282904.2 linkc.371A>G p.Gln124Arg missense_variant Exon 5 of 5 NP_001269833.1 P41145-2
LOC105375836NR_188096.1 linkn.2514T>C non_coding_transcript_exon_variant Exon 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OPRK1ENST00000265572.8 linkc.638A>G p.Gln213Arg missense_variant Exon 4 of 4 1 NM_000912.5 ENSP00000265572.3 P41145-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000442
AC:
1
AN:
226428
AF XY:
0.00000819
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000962
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000629
AC:
9
AN:
1431278
Hom.:
0
Cov.:
31
AF XY:
0.00000846
AC XY:
6
AN XY:
708828
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32134
American (AMR)
AF:
0.00
AC:
0
AN:
39860
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24336
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39310
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81862
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52764
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5576
European-Non Finnish (NFE)
AF:
0.00000821
AC:
9
AN:
1096654
Other (OTH)
AF:
0.00
AC:
0
AN:
58782
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152114
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41442
American (AMR)
AF:
0.00
AC:
0
AN:
15262
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 25, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.638A>G (p.Q213R) alteration is located in exon 4 (coding exon 3) of the OPRK1 gene. This alteration results from a A to G substitution at nucleotide position 638, causing the glutamine (Q) at amino acid position 213 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
0.18
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Benign
0.62
DEOGEN2
Benign
0.15
.;.;T;.;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
D;D;.;.;D
M_CAP
Benign
0.025
T
MetaRNN
Uncertain
0.44
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
.;.;L;.;L
PhyloP100
8.0
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.8
.;.;N;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.42
.;.;T;T;T
Sift4G
Benign
0.57
T;T;T;T;T
Polyphen
0.025
.;.;B;.;B
Vest4
0.60
MutPred
0.39
.;.;Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);
MVP
0.41
MPC
1.0
ClinPred
0.30
T
GERP RS
4.5
Varity_R
0.44
gMVP
0.79
Mutation Taster
=29/71
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.21
Position offset: -9

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

Publications

Other links and lift over

dbSNP: rs747120162; hg19: chr8-54142362; API