rs1199960069

Variant names:

• chr6-88144223-A-G
• rs1199960069
• NM_016083.6:c.1052T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016083.6(CNR1):​c.1052T>C​(p.Val351Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V351L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNR1 NM_016083.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3204521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR1	NM_016083.6	c.1052T>C	p.Val351Ala	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.1052T>C	p.Val351Ala	missense_variant	Exon 2 of 2	1	NM_016083.6	ENSP00000358513.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1052T>C (p.V351A) alteration is located in exon 2 (coding exon 1) of the CNR1 gene. This alteration results from a T to C substitution at nucleotide position 1052, causing the valine (V) at amino acid position 351 to be replaced by an alanine (A). 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	0.31
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T;T;.;T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	.;.;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L;L;L;.;L
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.58	P;P;P;B;P
Vest4		0.50
MutPred		0.56		Gain of sheet (P = 0.0507);Gain of sheet (P = 0.0507);Gain of sheet (P = 0.0507);.;Gain of sheet (P = 0.0507);
MVP		0.85
ClinPred		0.69	D
GERP RS		6.0
Varity_R		0.44
gMVP		0.95
Mutation Taster		=44/56	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: rs1199960069; hg19: chr6-88853942;