chr6-154039729-C-CCGG

Variant names:

• chr6-154039729-C-CCGG
• rs9282818
• NM_000914.5:c.187_189dupGGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PM4_Supporting BP6_Moderate BS2

The NM_000914.5(OPRM1):​c.187_189dupGGC​(p.Gly63dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,610,914 control chromosomes in the GnomAD database, including 54 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (53 hom.)
• Consequence: OPRM1 NM_000914.5 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28
• Publications: 1 publications found

Genes affected

OPRM1 (HGNC:8156): (opioid receptor mu 1) This gene encodes one of at least three opioid receptors in humans; the mu opioid receptor (MOR). The MOR is the principal target of endogenous opioid peptides and opioid analgesic agents such as beta-endorphin and enkephalins. The MOR also has an important role in dependence to other drugs of abuse, such as nicotine, cocaine, and alcohol via its modulation of the dopamine system. The NM_001008503.2:c.118A>G allele has been associated with opioid and alcohol addiction and variations in pain sensitivity but evidence for it having a causal role is conflicting. Multiple transcript variants encoding different isoforms have been found for this gene. Though the canonical MOR belongs to the superfamily of 7-transmembrane-spanning G-protein-coupled receptors some isoforms of this gene have only 6 transmembrane domains. [provided by RefSeq, Oct 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000914.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 6-154039729-C-CCGG is Benign according to our data. Variant chr6-154039729-C-CCGG is described in ClinVar as Likely_benign. ClinVar VariationId is 2657042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 53 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRM1	NM_000914.5	MANE Select	c.187_189dupGGC	p.Gly63dup	conservative_inframe_insertion	Exon 1 of 4	NP_000905.3
	OPRM1	NM_001145279.4		c.466_468dupGGC	p.Gly156dup	conservative_inframe_insertion	Exon 3 of 6	NP_001138751.1
	OPRM1	NM_001285524.1		c.466_468dupGGC	p.Gly156dup	conservative_inframe_insertion	Exon 2 of 5	NP_001272453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRM1	ENST00000330432.12	TSL:1 MANE Select	c.187_189dupGGC	p.Gly63dup	conservative_inframe_insertion	Exon 1 of 4	ENSP00000328264.7
	OPRM1	ENST00000434900.6	TSL:1	c.466_468dupGGC	p.Gly156dup	conservative_inframe_insertion	Exon 3 of 6	ENSP00000394624.2
	OPRM1	ENST00000360422.8	TSL:1	c.373_375dupGGC	p.Gly125dup	conservative_inframe_insertion	Exon 1 of 4	ENSP00000353598.5

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 780 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00648 AC: 1598 AN: 246478 AF XY: 0.00690

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00534

Gnomad NFE exome AF: 0.00903

Gnomad OTH exome AF: 0.00713

GnomAD4 exome AF: 0.00677 AC: 9881 AN: 1458570 Hom.: 53 Cov.: 32 AF XY: 0.00690 AC XY: 5007 AN XY: 725730

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00277 AC: 124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00967 AC: 834 AN: 86252

European-Finnish (FIN) AF: 0.00626 AC: 314 AN: 50150

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00725 AC: 8063 AN: 1111986

Other (OTH) AF: 0.00629 AC: 380 AN: 60374

GnomAD4 genome AF: 0.00511 AC: 779 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74500

African (AFR) AF: 0.00161 AC: 67 AN: 41586

American (AMR) AF: 0.00425 AC: 65 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00786 AC: 535 AN: 68036

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00642 Hom.: 2

Bravo AF: 0.00497

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00895

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OPRM1: BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=80/20	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9282818; hg19: chr6-154360864;