8-53250967-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

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]

ACMG classification

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/exons	MANE	UniProt
OPRK1	NM_000912.5	c.71C>G	p.Pro24Arg	missense_variant	2/4	ENST00000265572.8
OPRK1	NM_001318497.2	c.71C>G	p.Pro24Arg	missense_variant	2/4
OPRK1	NM_001282904.2	c.-371C>G		5_prime_UTR_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRK1	ENST00000265572.8	c.71C>G	p.Pro24Arg	missense_variant	2/4	1	NM_000912.5	P1
OPRK1	ENST00000520287.5	c.71C>G	p.Pro24Arg	missense_variant	1/3	1		P1
OPRK1	ENST00000522508.1	c.71C>G	p.Pro24Arg	missense_variant, NMD_transcript_variant	2/5	1
OPRK1	ENST00000673285.2	c.71C>G	p.Pro24Arg	missense_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152252 Hom.: 0 Cov.: 32

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: 23 AN: 227052 Hom.: 0 AF XY: 0.0000961 AC XY: 12 AN XY: 124930

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: 67 AN: 1454612 Hom.: 1 Cov.: 31 AF XY: 0.0000456 AC XY: 33 AN XY: 722978

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: 17 AN: 152370 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74502

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.: 0

Bravo AF: 0.000147

ExAC AF: 0.000126 AC: 15

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

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	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.46	T;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.90	N;N
PrimateAI	Uncertain	0.64	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	T
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

Other links and lift over

dbSNP: rs199919204; hg19: chr8-54163527;