rs780608074

Variant names:

• chr6-88144842-G-A
• rs780608074
• NM_016083.6:c.433C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-88144842-G-A
• chr6-88144842-G-T

Variant summary

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

The NM_016083.6(CNR1):​c.433C>T​(p.Arg145Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,818 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. R145S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CNR1 NM_016083.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

CNR1 (HGNC:2159): (cannabinoid receptor 1) This gene encodes one of two cannabinoid receptors. The cannabinoids, principally delta-9-tetrahydrocannabinol and synthetic analogs, are psychoactive ingredients of marijuana. The cannabinoid receptors are members of the guanine-nucleotide-binding protein (G-protein) coupled receptor family, which inhibit adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. The two receptors have been found to be involved in the cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana. Multiple transcript variants encoding two different protein isoforms have been described for this gene. [provided by RefSeq, May 2009]

ENSG00000298549 (HGNC:):

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, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR1	NM_016083.6	c.433C>T	p.Arg145Cys	missense_variant	Exon 2 of 2	ENST00000369501.3	NP_057167.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNR1	ENST00000369501.3	c.433C>T	p.Arg145Cys	missense_variant	Exon 2 of 2	1	NM_016083.6	ENSP00000358513.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461818 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;D;D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;.;.;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.4	M;M;M;.;M
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.4	D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.036	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.77
MutPred		0.69		Loss of disorder (P = 0.052);Loss of disorder (P = 0.052);Loss of disorder (P = 0.052);.;Loss of disorder (P = 0.052);
MVP		0.86
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		-0.034	Neutral
Varity_R		0.54
gMVP		0.92
Mutation Taster		=33/67	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

dbSNP: rs780608074; hg19: chr6-88854561; COSMIC: COSV62989256; COSMIC: COSV62989256;