8-53229320-C-T

Position:

• chr8-53229320-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000912.5(OPRK1):​c.1120G>A​(p.Asp374Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,846 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.019 (92 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (79 hom.)
• Consequence: OPRK1 NM_000912.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.60

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002861768).
• BP6: Variant 8-53229320-C-T is Benign according to our data. Variant chr8-53229320-C-T is described in ClinVar as [Benign]. Clinvar id is 790058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPRK1	NM_000912.5	c.1120G>A	p.Asp374Asn	missense_variant	4/4	ENST00000265572.8	NP_000903.2
LOC105375836	XR_928877.2	n.2032C>T		non_coding_transcript_exon_variant	3/3
OPRK1	NM_001318497.2	c.1120G>A	p.Asp374Asn	missense_variant	4/4		NP_001305426.1
OPRK1	NM_001282904.2	c.853G>A	p.Asp285Asn	missense_variant	5/5		NP_001269833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPRK1	ENST00000265572.8	c.1120G>A	p.Asp374Asn	missense_variant	4/4	1	NM_000912.5	ENSP00000265572	P1
	ENST00000524425.1	n.670+12816C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2856 AN: 152202 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00524 AC: 1316 AN: 251002 Hom.: 31 AF XY: 0.00385 AC XY: 522 AN XY: 135634

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00196 AC: 2869 AN: 1461526 Hom.: 79 Cov.: 32 AF XY: 0.00168 AC XY: 1218 AN XY: 727030

Gnomad4 AFR exome AF: 0.0673

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.0188 AC: 2857 AN: 152320 Hom.: 92 Cov.: 32 AF XY: 0.0185 AC XY: 1381 AN XY: 74484

Gnomad4 AFR AF: 0.0649

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00171 Hom.: 7

Bravo AF: 0.0215

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0640 AC: 282

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00630 AC: 765

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.91	D;D;.;.;D
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	.;.;M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	.;.;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	.;.;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D;D
Polyphen		0.10	.;.;B;.;B
Vest4		0.15
MVP		0.86
MPC		0.37
ClinPred		0.046	T
GERP RS		5.8
Varity_R		0.093
gMVP		0.25

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: rs9282808; hg19: chr8-54141880;