NM_000912.5:c.35C>T

Variant names:

• chr8-53251003-G-A
• rs1007918697
• NM_000912.5:c.35C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000912.5(OPRK1):​c.35C>T​(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,573,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: OPRK1 NM_000912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.992

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102481365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRK1	NM_000912.5	c.35C>T	p.Pro12Leu	missense_variant	Exon 2 of 4	ENST00000265572.8	NP_000903.2
OPRK1	NM_001282904.2	c.-407C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5		NP_001269833.1
OPRK1	NM_001318497.2	c.35C>T	p.Pro12Leu	missense_variant	Exon 2 of 4		NP_001305426.1
OPRK1	NM_001282904.2	c.-407C>T		5_prime_UTR_variant	Exon 2 of 5		NP_001269833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRK1	ENST00000265572.8	c.35C>T	p.Pro12Leu	missense_variant	Exon 2 of 4	1	NM_000912.5	ENSP00000265572.3
OPRK1	ENST00000520287.5	c.35C>T	p.Pro12Leu	missense_variant	Exon 1 of 3	1		ENSP00000429706.1
OPRK1	ENST00000522508.1	n.35C>T		non_coding_transcript_exon_variant	Exon 2 of 5	1		ENSP00000428231.1
OPRK1	ENST00000673285.2	c.35C>T	p.Pro12Leu	missense_variant	Exon 2 of 4			ENSP00000500765.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1421574 Hom.: 0 Cov.: 31 AF XY: 0.0000128 AC XY: 9 AN XY: 703606

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000833

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000128

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35C>T (p.P12L) alteration is located in exon 2 (coding exon 1) of the OPRK1 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the proline (P) at amino acid position 12 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	0.089
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.68	T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	.;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.44	.;N;N
REVEL	Benign	0.13
Sift	Benign	0.078	.;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.20
MutPred		0.31		Loss of disorder (P = 0.019);Loss of disorder (P = 0.019);Loss of disorder (P = 0.019);
MVP		0.78
MPC		0.30
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.052
gMVP		0.51

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: rs1007918697; hg19: chr8-54163563;