chr1-23874672-G-A

Variant names:

• chr1-23874672-G-A
• rs2229579
• NM_001841.3:c.946C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001841.3(CNR2):​c.946C>T​(p.His316Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0952 in 1,614,024 control chromosomes in the GnomAD database, including 8,083 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.077 (606 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7477 hom.)
• Consequence: CNR2 NM_001841.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0330
• Publications: 53 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036177933).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001841.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNR2	NM_001841.3	MANE Select	c.946C>T	p.His316Tyr	missense	Exon 2 of 2	NP_001832.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNR2	ENST00000374472.5	TSL:1 MANE Select	c.946C>T	p.His316Tyr	missense	Exon 2 of 2	ENSP00000363596.4

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 11744 AN: 152046 Hom.: 604 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.0819

GnomAD2 exomes AF: 0.100 AC: 25220 AN: 251462 AF XY: 0.102

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0950

Gnomad OTH exome AF: 0.0927

GnomAD4 exome AF: 0.0971 AC: 141916 AN: 1461860 Hom.: 7477 Cov.: 65 AF XY: 0.0980 AC XY: 71259 AN XY: 727228

African (AFR) AF: 0.0142 AC: 475 AN: 33480

American (AMR) AF: 0.108 AC: 4837 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3354 AN: 26136

East Asian (EAS) AF: 0.178 AC: 7048 AN: 39694

South Asian (SAS) AF: 0.123 AC: 10573 AN: 86256

European-Finnish (FIN) AF: 0.0430 AC: 2299 AN: 53418

Middle Eastern (MID) AF: 0.0563 AC: 325 AN: 5768

European-Non Finnish (NFE) AF: 0.0963 AC: 107036 AN: 1111990

Other (OTH) AF: 0.0988 AC: 5969 AN: 60394

GnomAD4 genome AF: 0.0773 AC: 11756 AN: 152164 Hom.: 606 Cov.: 32 AF XY: 0.0769 AC XY: 5718 AN XY: 74390

African (AFR) AF: 0.0185 AC: 767 AN: 41524

American (AMR) AF: 0.112 AC: 1709 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3470

East Asian (EAS) AF: 0.207 AC: 1069 AN: 5164

South Asian (SAS) AF: 0.137 AC: 661 AN: 4814

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10602

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0951 AC: 6466 AN: 67984

Other (OTH) AF: 0.0900 AC: 190 AN: 2110

Alfa AF: 0.0930 Hom.: 2050

Bravo AF: 0.0793

TwinsUK AF: 0.0893 AC: 331

ALSPAC AF: 0.0939 AC: 362

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.0999 AC: 859

ExAC AF: 0.0972 AC: 11806

Asia WGS AF: 0.170 AC: 591 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.23
DANN	Benign	0.65
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.033
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.016
Sift	Benign	0.14	T
Sift4G	Benign	0.40	T
Polyphen		0.30	B
Vest4		0.020
ClinPred		0.0025	T
GERP RS		0.73
Varity_R		0.073
gMVP		0.13
Mutation Taster		=98/2	polymorphism (auto)

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: rs2229579; hg19: chr1-24201162; COSMIC: COSV65692628;