NM_016083.6:c.1366A>C

Variant names:

• chr6-88143909-T-G
• rs141056981
• NM_016083.6:c.1366A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016083.6(CNR1):​c.1366A>C​(p.Ile456Leu) 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. Variant has been reported in ClinVar 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: 7.67
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24055105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR1	NM_016083.6	c.1366A>C	p.Ile456Leu	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.1366A>C	p.Ile456Leu	missense_variant	Exon 2 of 2	1	NM_016083.6	ENSP00000358513.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1366A>C (p.I456L) alteration is located in exon 2 (coding exon 1) of the CNR1 gene. This alteration results from a A to C substitution at nucleotide position 1366, causing the isoleucine (I) at amino acid position 456 to be replaced by a leucine (L). 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	0.23
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;T;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;.;.;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L;L;L;.;L
PhyloP100		7.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.23	N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.025	D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D
Polyphen		0.29	B;B;B;B;B
Vest4		0.49
MutPred		0.17		Loss of methylation at K458 (P = 0.1082);Loss of methylation at K458 (P = 0.1082);Loss of methylation at K458 (P = 0.1082);.;Loss of methylation at K458 (P = 0.1082);
MVP		0.79
ClinPred		0.77	D
GERP RS		5.9
Varity_R		0.27
gMVP		0.36
Mutation Taster		=32/68	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: rs141056981; hg19: chr6-88853628;