Genetic Variant NM_000912.5:c.948C>G (chr8-53229492-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000912.5(OPRK1):c.948C>G(p.Ile316Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I316I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OPRK1
NM_000912.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.363

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]

OPRK1 links:

LOC105375836 (HGNC:):

LOC105375836 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3911394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRK1	NM_000912.5 link	c.948C>G	p.Ile316Met	missense_variant	Exon 4 of 4	ENST00000265572.8	NP_000903.2	P41145-1
OPRK1	NM_001318497.2 link	c.948C>G	p.Ile316Met	missense_variant	Exon 4 of 4		NP_001305426.1	P41145A0A5F9ZI09
OPRK1	NM_001282904.2 link	c.681C>G	p.Ile227Met	missense_variant	Exon 5 of 5		NP_001269833.1	P41145-2
LOC105375836	NR_188096.1 link	n.2204G>C		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRK1	ENST00000265572.8 link	c.948C>G	p.Ile316Met	missense_variant	Exon 4 of 4	1	NM_000912.5	ENSP00000265572.3		P41145-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;T;.;T

Eigen

Benign

0.16

Eigen_PC

Benign

-0.0037

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.97

D;D;.;.;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.39

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.2

.;.;M;.;M

PhyloP100

-0.36

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

.;.;N;N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0020

.;.;D;D;D

Sift4G

Benign

0.23

T;T;T;T;T

Polyphen

1.0

.;.;D;.;D

Vest4

0.51

MutPred

0.52

.;.;Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);

MVP

0.85

MPC

0.98

ClinPred

0.98

GERP RS

-2.2

Varity_R

0.87

gMVP

0.38

Mutation Taster

=51/49

polymorphism

(source)

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

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NM_000912.5:c.948C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over