rs2128807595

Variant names:

• chr8-53229717-G-C
• rs2128807595
• NM_000912.5:c.723C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000912.5(OPRK1):​c.723C>G​(p.Ile241Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPRK1 NM_000912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

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]

LOC105375836 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000912.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRK1	NM_000912.5	MANE Select	c.723C>G	p.Ile241Met	missense	Exon 4 of 4	NP_000903.2
	OPRK1	NM_001318497.2		c.723C>G	p.Ile241Met	missense	Exon 4 of 4	NP_001305426.1	A0A5F9ZI09
	OPRK1	NM_001282904.2		c.456C>G	p.Ile152Met	missense	Exon 5 of 5	NP_001269833.1	P41145-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRK1	ENST00000265572.8	TSL:1 MANE Select	c.723C>G	p.Ile241Met	missense	Exon 4 of 4	ENSP00000265572.3	P41145-1
	OPRK1	ENST00000520287.5	TSL:1	c.723C>G	p.Ile241Met	missense	Exon 3 of 3	ENSP00000429706.1	P41145-1
	OPRK1	ENST00000524278.5	TSL:1	c.456C>G	p.Ile152Met	missense	Exon 3 of 3	ENSP00000430923.1	P41145-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.67		Loss of stability (P = 0.1614)
MVP		0.84
MPC		1.0
ClinPred		0.94	D
GERP RS		0.79
Varity_R		0.82
gMVP		0.77
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs2128807595; hg19: chr8-54142277;