Genetic Variant NM_001841.3:c.397C>A (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

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	P34972

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	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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over