8-53250820-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000912.5(OPRK1):c.218G>C(p.Gly73Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: OPRK1 NM_000912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRK1	NM_000912.5	c.218G>C	p.Gly73Ala	missense_variant	2/4	ENST00000265572.8
OPRK1	NM_001318497.2	c.218G>C	p.Gly73Ala	missense_variant	2/4
OPRK1	NM_001282904.2	c.-224G>C		5_prime_UTR_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRK1	ENST00000265572.8	c.218G>C	p.Gly73Ala	missense_variant	2/4	1	NM_000912.5	P1
OPRK1	ENST00000520287.5	c.218G>C	p.Gly73Ala	missense_variant	1/3	1		P1
OPRK1	ENST00000522508.1	c.218G>C	p.Gly73Ala	missense_variant, NMD_transcript_variant	2/5	1
OPRK1	ENST00000673285.2	c.218G>C	p.Gly73Ala	missense_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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

Sep 20, 2023

The c.218G>C (p.G73A) alteration is located in exon 2 (coding exon 1) of the OPRK1 gene. This alteration results from a G to C substitution at nucleotide position 218, causing the glycine (G) at amino acid position 73 to be replaced by an alanine (A). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.078	.;B;B
Vest4		0.72
MutPred		0.87		.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.78
MPC		0.32
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1308194118; hg19: chr8-54163380;