dbSNP rs201087852: CNR2:p.Val159Phe (chr1-23875143-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001841.3(CNR2):c.475G>T(p.Val159Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 1,460,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CNR2
NM_001841.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.337

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR2	NM_001841.3 link	c.475G>T	p.Val159Phe	missense_variant	Exon 2 of 2	ENST00000374472.5	NP_001832.1	P34972A0A024RAH7
CNR2	XM_011540629.4 link	c.475G>T	p.Val159Phe	missense_variant	Exon 2 of 2		XP_011538931.1	P34972A0A024RAH7
CNR2	XM_017000261.3 link	c.475G>T	p.Val159Phe	missense_variant	Exon 3 of 3		XP_016855750.1	P34972A0A024RAH7
CNR2	XM_047444833.1 link	c.475G>T	p.Val159Phe	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.475G>T	p.Val159Phe	missense_variant	Exon 2 of 2	1	NM_001841.3	ENSP00000363596.4		P34972

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249476

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1460170

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25896

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

85996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111060

Other (OTH)

AF:

0.0000497

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.475G>T (p.V159F) alteration is located in exon 2 (coding exon 1) of the CNR2 gene. This alteration results from a G to T substitution at nucleotide position 475, causing the valine (V) at amino acid position 159 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.11

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.71

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.7

PhyloP100

0.34

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.27

Sift

Uncertain

0.018

Sift4G

Uncertain

0.033

Polyphen

0.72

Vest4

0.18

MutPred

0.71

Loss of MoRF binding (P = 0.1972);

MVP

0.79

ClinPred

0.38

GERP RS

2.6

Varity_R

0.29

gMVP

0.53

Mutation Taster

=47/53

disease causing

(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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rs201087852

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over