Genetic Variant NM_001841.3:c.846T>C (chr1-23874772-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001841.3(CNR2):c.846T>C(p.Ala282Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,860 control chromosomes in the GnomAD database, including 287,075 homozygotes. In-silico tool predicts 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 ( 31020 hom., cov: 32)

Exomes 𝑓: 0.59 ( 256055 hom. )

Consequence

CNR2
NM_001841.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.431

Publications

23 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP7

Synonymous conserved (PhyloP=0.431 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR2	NM_001841.3 link	c.846T>C	p.Ala282Ala	synonymous_variant	Exon 2 of 2	ENST00000374472.5	NP_001832.1	P34972A0A024RAH7
CNR2	XM_011540629.4 link	c.846T>C	p.Ala282Ala	synonymous_variant	Exon 2 of 2		XP_011538931.1	P34972A0A024RAH7
CNR2	XM_017000261.3 link	c.846T>C	p.Ala282Ala	synonymous_variant	Exon 3 of 3		XP_016855750.1	P34972A0A024RAH7
CNR2	XM_047444833.1 link	c.846T>C	p.Ala282Ala	synonymous_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.846T>C	p.Ala282Ala	synonymous_variant	Exon 2 of 2	1	NM_001841.3	ENSP00000363596.4		P34972

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96436

AN:

151958

Hom.:

31010

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.550

Gnomad AMR

AF:

0.641

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.526

Gnomad SAS

AF:

0.713

Gnomad FIN

AF:

0.576

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.574

Gnomad OTH

AF:

0.619

GnomAD2 exomes

AF:

0.617

AC:

155135

AN:

251322

AF XY:

0.618

show subpopulations

Gnomad AFR exome

AF:

0.761

Gnomad AMR exome

AF:

0.686

Gnomad ASJ exome

AF:

0.575

Gnomad EAS exome

AF:

0.529

Gnomad FIN exome

AF:

0.583

Gnomad NFE exome

AF:

0.574

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.589

AC:

861510

AN:

1461784

Hom.:

256055

Cov.:

AF XY:

0.593

AC XY:

431033

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.766

AC:

25628

AN:

33478

American (AMR)

AF:

0.680

AC:

30395

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.573

AC:

14982

AN:

26134

East Asian (EAS)

AF:

0.569

AC:

22581

AN:

39686

South Asian (SAS)

AF:

0.719

AC:

62042

AN:

86256

European-Finnish (FIN)

AF:

0.574

AC:

30635

AN:

53408

Middle Eastern (MID)

AF:

0.710

AC:

4093

AN:

5768

European-Non Finnish (NFE)

AF:

0.571

AC:

635312

AN:

1111942

Other (OTH)

AF:

0.593

AC:

35842

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

20237

40473

60710

80946

101183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17784

35568

53352

71136

88920

<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:

0.634

AC:

96488

AN:

152076

Hom.:

31020

Cov.:

AF XY:

0.638

AC XY:

47402

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.756

AC:

31401

AN:

41520

American (AMR)

AF:

0.641

AC:

9802

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

2014

AN:

3468

East Asian (EAS)

AF:

0.525

AC:

2703

AN:

5152

South Asian (SAS)

AF:

0.714

AC:

3444

AN:

4826

European-Finnish (FIN)

AF:

0.576

AC:

6099

AN:

10580

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.574

AC:

39028

AN:

67934

Other (OTH)

AF:

0.613

AC:

1294

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

1844

3688

5532

7376

9220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.598

Hom.:

43487

Bravo

AF:

0.644

Asia WGS

AF:

0.632

AC:

2197

AN:

3478

EpiCase

AF:

0.578

EpiControl

AF:

0.591

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.6

(source)

DANN

Benign

0.69

PhyloP100

0.43

Mutation Taster

=99/1

polymorphism (auto)

(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