1-23875421-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001841.3(CNR2):c.197G>A(p.Arg66Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,614,198 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (19 hom.)
• Consequence: CNR2 NM_001841.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.552

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004694581).
• BP6: Variant 1-23875421-C-T is Benign according to our data. Variant chr1-23875421-C-T is described in ClinVar as [Benign]. Clinvar id is 785933.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00939 (1431/152326) while in subpopulation AFR AF= 0.0309 (1284/41590). AF 95% confidence interval is 0.0295. There are 27 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNR2	NM_001841.3	c.197G>A	p.Arg66Gln	missense_variant	2/2	ENST00000374472.5
CNR2	XM_011540629.4	c.197G>A	p.Arg66Gln	missense_variant	2/2
CNR2	XM_017000261.3	c.197G>A	p.Arg66Gln	missense_variant	3/3
CNR2	XM_047444833.1	c.197G>A	p.Arg66Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNR2	ENST00000374472.5	c.197G>A	p.Arg66Gln	missense_variant	2/2	1	NM_001841.3	P1

Frequencies

GnomAD3 genomes AF: 0.00938 AC: 1427 AN: 152208 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00298 AC: 747 AN: 250902 Hom.: 14 AF XY: 0.00228 AC XY: 310 AN XY: 135810

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00128 AC: 1871 AN: 1461872 Hom.: 19 Cov.: 68 AF XY: 0.00116 AC XY: 844 AN XY: 727232

Gnomad4 AFR exome AF: 0.0309

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00939 AC: 1431 AN: 152326 Hom.: 27 Cov.: 33 AF XY: 0.00948 AC XY: 706 AN XY: 74476

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00210 Hom.: 3

Bravo AF: 0.0103

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0318 AC: 140

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00349 AC: 424

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	9.2
Dann	Benign	0.91
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.26
Sift	Benign	0.35	T
Sift4G	Benign	0.36	T
Polyphen		0.23	B
Vest4		0.061
MVP		0.75
ClinPred		0.015	T
GERP RS		0.65
Varity_R		0.21
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs61996280; hg19: chr1-24201911;