NM_001841.3:c.397C>A

Variant names:

• chr1-23875221-G-T
• rs41311993
• NM_001841.3:c.397C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001841.3(CNR2):​c.397C>A​(p.Leu133Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,614,172 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (30 hom.)
• Consequence: CNR2 NM_001841.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.742
• Publications: 17 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009951115).
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001841.3. 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
	CNR2	NM_001841.3	MANE Select	c.397C>A	p.Leu133Ile	missense	Exon 2 of 2	NP_001832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNR2	ENST00000374472.5	TSL:1 MANE Select	c.397C>A	p.Leu133Ile	missense	Exon 2 of 2	ENSP00000363596.4

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 407 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00379 AC: 953 AN: 251154 AF XY: 0.00400

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00478

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00450 AC: 6578 AN: 1461846 Hom.: 30 Cov.: 69 AF XY: 0.00447 AC XY: 3254 AN XY: 727222

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 460 AN: 26126

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

South Asian (SAS) AF: 0.00435 AC: 375 AN: 86256

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53412

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5766

European-Non Finnish (NFE) AF: 0.00480 AC: 5340 AN: 1111996

Other (OTH) AF: 0.00440 AC: 266 AN: 60390

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74476

African (AFR) AF: 0.000722 AC: 30 AN: 41580

American (AMR) AF: 0.00105 AC: 16 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00417 AC: 284 AN: 68032

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00458 Hom.: 6

Bravo AF: 0.00267

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00363 AC: 441

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00516

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.00059
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.74
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.11
Sift	Benign	0.98	T
Sift4G	Benign	0.72	T
Polyphen		0.88	P
Vest4		0.079
MVP		0.67
ClinPred		0.039	T
GERP RS		5.8
Varity_R		0.52
gMVP		0.26
Mutation Taster		=87/13	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: rs41311993; hg19: chr1-24201711;