NM_000912.5:c.676A>C

Variant names:

• chr8-53229764-T-G
• rs1563326168
• NM_000912.5:c.676A>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.676A>C​(p.Met226Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: OPRK1 NM_000912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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

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=0.18186378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRK1	NM_000912.5	c.676A>C	p.Met226Leu	missense_variant	Exon 4 of 4	ENST00000265572.8	NP_000903.2
OPRK1	NM_001318497.2	c.676A>C	p.Met226Leu	missense_variant	Exon 4 of 4		NP_001305426.1
OPRK1	NM_001282904.2	c.409A>C	p.Met137Leu	missense_variant	Exon 5 of 5		NP_001269833.1
LOC105375836	NR_188096.1	n.2476T>G		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	c.676A>C	p.Met226Leu	missense_variant	Exon 4 of 4	1	NM_000912.5	ENSP00000265572.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.676A>C (p.M226L) alteration is located in exon 4 (coding exon 3) of the OPRK1 gene. This alteration results from a A to C substitution at nucleotide position 676, causing the methionine (M) at amino acid position 226 to be replaced by a leucine (L). 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	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.069	.;.;T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;.;.;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	.;.;N;.;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.57	.;.;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.94	.;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;.;B;.;B
Vest4		0.35
MutPred		0.56		.;.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);
MVP		0.54
MPC		0.28
ClinPred		0.61	D
GERP RS		4.5
Varity_R		0.33
gMVP		0.79

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: rs1563326168; hg19: chr8-54142324;