1-23875430-T-C

Variant names:

• chr1-23875430-T-C
• rs2501432
• NM_001841.3:c.188A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001841.3(CNR2):​c.188A>G​(p.Gln63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,492 control chromosomes in the GnomAD database, including 286,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (30831 hom., cov: 33)
  • Exomes 𝑓: 0.59 (256031 hom.)
• Consequence: CNR2 NM_001841.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 63 publications found

Genes affected

CNR2 (HGNC:2160): (cannabinoid receptor 2) The cannabinoid delta-9-tetrahydrocannabinol is the principal psychoactive ingredient of marijuana. The proteins encoded by this gene and the cannabinoid receptor 1 (brain) (CNR1) gene have the characteristics of a guanine nucleotide-binding protein (G-protein)-coupled receptor for cannabinoids. They inhibit adenylate cyclase activity in a dose-dependent, stereoselective, and pertussis toxin-sensitive manner. These proteins have been found to be involved in the cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana. The cannabinoid receptors are members of family 1 of the G-protein-coupled receptors. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1362777E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR2	NM_001841.3	c.188A>G	p.Gln63Arg	missense_variant	Exon 2 of 2	ENST00000374472.5	NP_001832.1
CNR2	XM_011540629.4	c.188A>G	p.Gln63Arg	missense_variant	Exon 2 of 2		XP_011538931.1
CNR2	XM_017000261.3	c.188A>G	p.Gln63Arg	missense_variant	Exon 3 of 3		XP_016855750.1
CNR2	XM_047444833.1	c.188A>G	p.Gln63Arg	missense_variant	Exon 2 of 2		XP_047300789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNR2	ENST00000374472.5	c.188A>G	p.Gln63Arg	missense_variant	Exon 2 of 2	1	NM_001841.3	ENSP00000363596.4

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96089 AN: 151626 Hom.: 30821 Cov.: 33

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.618

GnomAD2 exomes AF: 0.617 AC: 154394 AN: 250392 AF XY: 0.617

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.589 AC: 861482 AN: 1461748 Hom.: 256031 Cov.: 67 AF XY: 0.593 AC XY: 430994 AN XY: 727150

African (AFR) AF: 0.765 AC: 25628 AN: 33480

American (AMR) AF: 0.680 AC: 30386 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 14983 AN: 26136

East Asian (EAS) AF: 0.569 AC: 22584 AN: 39686

South Asian (SAS) AF: 0.719 AC: 62044 AN: 86256

European-Finnish (FIN) AF: 0.574 AC: 30621 AN: 53392

Middle Eastern (MID) AF: 0.710 AC: 4092 AN: 5766

European-Non Finnish (NFE) AF: 0.571 AC: 635301 AN: 1111936

Other (OTH) AF: 0.594 AC: 35843 AN: 60386

GnomAD4 genome AF: 0.634 AC: 96141 AN: 151744 Hom.: 30831 Cov.: 33 AF XY: 0.637 AC XY: 47195 AN XY: 74130

African (AFR) AF: 0.755 AC: 31262 AN: 41398

American (AMR) AF: 0.641 AC: 9777 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2011 AN: 3466

East Asian (EAS) AF: 0.523 AC: 2680 AN: 5126

South Asian (SAS) AF: 0.713 AC: 3439 AN: 4822

European-Finnish (FIN) AF: 0.575 AC: 6029 AN: 10494

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.574 AC: 38953 AN: 67870

Other (OTH) AF: 0.612 AC: 1293 AN: 2112

Alfa AF: 0.588 Hom.: 48283

Bravo AF: 0.644

TwinsUK AF: 0.561 AC: 2080

ALSPAC AF: 0.575 AC: 2215

ESP6500AA AF: 0.728 AC: 3208

ESP6500EA AF: 0.550 AC: 4732

ExAC AF: 0.617 AC: 74927

Asia WGS AF: 0.630 AC: 2190 AN: 3478

EpiCase AF: 0.578

EpiControl AF: 0.590

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.9
DANN	Benign	0.17
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000031	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Vest4		0.010
ClinPred		0.0023	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.069
Mutation Taster		=99/1	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: rs2501432; hg19: chr1-24201920; COSMIC: COSV65692458;