8-53229492-G-A

Variant names:

• chr8-53229492-G-A
• rs78517449
• NM_000912.5:c.948C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000912.5(OPRK1):​c.948C>T​(p.Ile316Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,614,192 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (80 hom.)
• Consequence: OPRK1 NM_000912.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.363
• Publications: 2 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 8-53229492-G-A is Benign according to our data. Variant chr8-53229492-G-A is described in ClinVar as [Benign]. Clinvar id is 790059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.363 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRK1	NM_000912.5	c.948C>T	p.Ile316Ile	synonymous_variant	Exon 4 of 4	ENST00000265572.8	NP_000903.2
OPRK1	NM_001318497.2	c.948C>T	p.Ile316Ile	synonymous_variant	Exon 4 of 4		NP_001305426.1
OPRK1	NM_001282904.2	c.681C>T	p.Ile227Ile	synonymous_variant	Exon 5 of 5		NP_001269833.1
LOC105375836	NR_188096.1	n.2204G>A		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.948C>T	p.Ile316Ile	synonymous_variant	Exon 4 of 4	1	NM_000912.5	ENSP00000265572.3

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2867 AN: 152208 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00525 AC: 1318 AN: 251216 AF XY: 0.00385

Gnomad AFR exome AF: 0.0712

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00197 AC: 2876 AN: 1461866 Hom.: 80 Cov.: 32 AF XY: 0.00168 AC XY: 1220 AN XY: 727224

African (AFR) AF: 0.0675 AC: 2259 AN: 33480

American (AMR) AF: 0.00364 AC: 163 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1112002

Other (OTH) AF: 0.00434 AC: 262 AN: 60392

GnomAD4 genome AF: 0.0188 AC: 2868 AN: 152326 Hom.: 94 Cov.: 32 AF XY: 0.0186 AC XY: 1385 AN XY: 74494

African (AFR) AF: 0.0651 AC: 2707 AN: 41558

American (AMR) AF: 0.00679 AC: 104 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68038

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0103 Hom.: 30

Bravo AF: 0.0216

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.4
DANN	Benign	0.81
PhyloP100		-0.36
Mutation Taster		=90/10	polymorphism (auto)

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: rs78517449; hg19: chr8-54142052; COSMIC: COSV104547669;