1-23875036-C-A

Variant names:

• chr1-23875036-C-A
• NM_001841.3:c.582G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001841.3(CNR2):​c.582G>T​(p.Trp194Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNR2 NM_001841.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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]

ACMG classification

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, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR2	NM_001841.3	c.582G>T	p.Trp194Cys	missense_variant	Exon 2 of 2	ENST00000374472.5	NP_001832.1
CNR2	XM_011540629.4	c.582G>T	p.Trp194Cys	missense_variant	Exon 2 of 2		XP_011538931.1
CNR2	XM_017000261.3	c.582G>T	p.Trp194Cys	missense_variant	Exon 3 of 3		XP_016855750.1
CNR2	XM_047444833.1	c.582G>T	p.Trp194Cys	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	c.582G>T	p.Trp194Cys	missense_variant	Exon 2 of 2	1	NM_001841.3	ENSP00000363596.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.582G>T (p.W194C) 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 582, causing the tryptophan (W) at amino acid position 194 to be replaced by a cysteine (C). 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.74		Loss of catalytic residue at L192 (P = 0.0037);
MVP		0.95
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.96
gMVP		0.94
Mutation Taster		=14/86	disease causing

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

Other links and lift over

hg19: chr1-24201526;