chr1-23875401-T-A

Position:

• chr1-23875401-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001841.3(CNR2):​c.217A>T​(p.Ile73Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNR2 NM_001841.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNR2	NM_001841.3	c.217A>T	p.Ile73Phe	missense_variant	2/2	ENST00000374472.5	NP_001832.1
CNR2	XM_011540629.4	c.217A>T	p.Ile73Phe	missense_variant	2/2		XP_011538931.1
CNR2	XM_017000261.3	c.217A>T	p.Ile73Phe	missense_variant	3/3		XP_016855750.1
CNR2	XM_047444833.1	c.217A>T	p.Ile73Phe	missense_variant	2/2		XP_047300789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNR2	ENST00000374472.5	c.217A>T	p.Ile73Phe	missense_variant	2/2	1	NM_001841.3	ENSP00000363596.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The c.217A>T (p.I73F) alteration is located in exon 2 (coding exon 1) of the CNR2 gene. This alteration results from a A to T substitution at nucleotide position 217, causing the isoleucine (I) at amino acid position 73 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	0.32
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.65		Gain of glycosylation at S75 (P = 0.1323);
MVP		0.76
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.91
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-24201891;