chr8-53229675-G-A

Variant names:

• chr8-53229675-G-A
• rs139043596
• NM_000912.5:c.765C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000912.5(OPRK1):​c.765C>T​(p.Ser255Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,614,118 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: OPRK1 NM_000912.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0230
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 8-53229675-G-A is Benign according to our data. Variant chr8-53229675-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 720427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.023 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.765C>T	p.Ser255Ser	synonymous	Exon 4 of 4	NP_000903.2
	OPRK1	NM_001318497.2		c.765C>T	p.Ser255Ser	synonymous	Exon 4 of 4	NP_001305426.1	A0A5F9ZI09
	OPRK1	NM_001282904.2		c.498C>T	p.Ser166Ser	synonymous	Exon 5 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.765C>T	p.Ser255Ser	synonymous	Exon 4 of 4	ENSP00000265572.3	P41145-1
	OPRK1	ENST00000520287.5	TSL:1	c.765C>T	p.Ser255Ser	synonymous	Exon 3 of 3	ENSP00000429706.1	P41145-1
	OPRK1	ENST00000524278.5	TSL:1	c.498C>T	p.Ser166Ser	synonymous	Exon 3 of 3	ENSP00000430923.1	P41145-2

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000641 AC: 161 AN: 251272 AF XY: 0.000736

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1461870 Hom.: 3 Cov.: 31 AF XY: 0.000539 AC XY: 392 AN XY: 727234

African (AFR) AF: 0.00140 AC: 47 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00746 AC: 43 AN: 5766

European-Non Finnish (NFE) AF: 0.000399 AC: 444 AN: 1112004

Other (OTH) AF: 0.00109 AC: 66 AN: 60390

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74432

African (AFR) AF: 0.000193 AC: 8 AN: 41542

American (AMR) AF: 0.00170 AC: 26 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68008

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

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.000608

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.7
DANN	Benign	0.79
PhyloP100		0.023
Mutation Taster		=88/12	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: rs139043596; hg19: chr8-54142235; COSMIC: COSV55570600;