dbSNP rs41311993: CNR2:p.Leu133Ile (chr1-23875221-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.742

Publications

17 publications found

Variant links:

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]

CNR2 links:

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ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR2	NM_001841.3 link	c.397C>A	p.Leu133Ile	missense_variant	Exon 2 of 2	ENST00000374472.5	NP_001832.1	P34972A0A024RAH7
CNR2	XM_011540629.4 link	c.397C>A	p.Leu133Ile	missense_variant	Exon 2 of 2		XP_011538931.1	P34972A0A024RAH7
CNR2	XM_017000261.3 link	c.397C>A	p.Leu133Ile	missense_variant	Exon 3 of 3		XP_016855750.1	P34972A0A024RAH7
CNR2	XM_047444833.1 link	c.397C>A	p.Leu133Ile	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 link	c.397C>A	p.Leu133Ile	missense_variant	Exon 2 of 2	1	NM_001841.3	ENSP00000363596.4		P34972

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

407

AN:

152208

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00447

AC XY:

3254

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00141

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

460

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00435

AC:

375

AN:

86256

European-Finnish (FIN)

AF:

0.000637

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00480

AC:

5340

AN:

1111996

Other (OTH)

AF:

0.00440

AC:

266

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

430

860

1290

1720

2150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00267

AC:

406

AN:

152326

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41580

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00417

AC:

284

AN:

68032

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00458

Hom.:

Bravo

AF:

0.00267

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00363

AC:

441

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00516

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.064

Eigen

Benign

-0.00059

Eigen_PC

Benign

0.074

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.77

M_CAP

Benign

0.011

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.41

PhyloP100

0.74

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.040

REVEL

Benign

0.11

Sift

Benign

0.98

Sift4G

Benign

0.72

Polyphen

0.88

Vest4

0.079

MVP

0.67

ClinPred

0.039

GERP RS

5.8

Varity_R

0.52

gMVP

0.26

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over