dbSNP rs142861964: CNR2:p.Ala199Pro (chr1-23875023-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001841.3(CNR2):c.595G>C(p.Ala199Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A199T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CNR2
NM_001841.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0120

Publications

7 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR2	NM_001841.3 link	c.595G>C	p.Ala199Pro	missense_variant	Exon 2 of 2	ENST00000374472.5	NP_001832.1	P34972A0A024RAH7
CNR2	XM_011540629.4 link	c.595G>C	p.Ala199Pro	missense_variant	Exon 2 of 2		XP_011538931.1	P34972A0A024RAH7
CNR2	XM_017000261.3 link	c.595G>C	p.Ala199Pro	missense_variant	Exon 3 of 3		XP_016855750.1	P34972A0A024RAH7
CNR2	XM_047444833.1 link	c.595G>C	p.Ala199Pro	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.595G>C	p.Ala199Pro	missense_variant	Exon 2 of 2	1	NM_001841.3	ENSP00000363596.4		P34972

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456472

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25594

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

85280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1109424

Other (OTH)

AF:

0.00

AC:

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.68

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.7

PhyloP100

0.012

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.50

Sift

Benign

0.11

Sift4G

Benign

0.083

Polyphen

0.88

Vest4

0.42

MutPred

0.82

Loss of stability (P = 0.0232);

MVP

0.83

ClinPred

0.50

GERP RS

3.0

Varity_R

0.89

gMVP

0.83

Mutation Taster

=77/23

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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rs142861964

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over