NM_000912.5:c.71C>G

Variant names:

• chr8-53250967-G-C
• rs199919204
• NM_000912.5:c.71C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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. 14/22 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
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.104914874).

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.71C>G	p.Pro24Arg	missense	Exon 2 of 4	NP_000903.2
	OPRK1	NM_001318497.2		c.71C>G	p.Pro24Arg	missense	Exon 2 of 4	NP_001305426.1	A0A5F9ZI09
	OPRK1	NM_001282904.2		c.-371C>G		5_prime_UTR	Exon 2 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.71C>G	p.Pro24Arg	missense	Exon 2 of 4	ENSP00000265572.3	P41145-1
	OPRK1	ENST00000520287.5	TSL:1	c.71C>G	p.Pro24Arg	missense	Exon 1 of 3	ENSP00000429706.1	P41145-1
	OPRK1	ENST00000522508.1	TSL:1	n.71C>G		non_coding_transcript_exon	Exon 2 of 5	ENSP00000428231.1	E5RJI5

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

GnomAD2 exomes AF: 0.000101 AC: 23 AN: 227052 AF XY: 0.0000961

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 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

African (AFR) AF: 0.0000903 AC: 3 AN: 33210

American (AMR) AF: 0.0000226 AC: 1 AN: 44160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39468

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85590

European-Finnish (FIN) AF: 0.000116 AC: 6 AN: 51908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000352 AC: 39 AN: 1108732

Other (OTH) AF: 0.000150 AC: 9 AN: 59954

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152370 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74502

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

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

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	0.079
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.062	T
Polyphen		0.0030	B
Vest4		0.36
MutPred		0.24		Loss of catalytic residue at P23 (P = 0.016)
MVP		0.83
MPC		0.31
ClinPred		0.034	T
GERP RS		3.1
PromoterAI		-0.0092	Neutral
Varity_R		0.062
gMVP		0.58
Mutation Taster		=81/19	polymorphism

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: rs199919204; hg19: chr8-54163527;