Genetic Variant CNR1:p.His304His (chr6-88144363-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_016083.6(CNR1):c.912C>T(p.His304His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,884 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0069 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 28 hom. )

Consequence

CNR1
NM_016083.6 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.815

Publications

1 publications found

Variant links:

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]

CNR1 links:

ENSG00000298549 (HGNC:):

ENSG00000298549 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 6-88144363-G-A is Benign according to our data. Variant chr6-88144363-G-A is described in ClinVar as [Benign]. Clinvar id is 771863.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.815 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00694 (1057/152264) while in subpopulation AFR AF = 0.02 (832/41538). AF 95% confidence interval is 0.0189. There are 17 homozygotes in GnomAd4. There are 509 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1057 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNR1	NM_016083.6 link	c.912C>T	p.His304His	synonymous_variant	Exon 2 of 2	ENST00000369501.3	NP_057167.2	P21554-1S5TLS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNR1	ENST00000369501.3 link	c.912C>T	p.His304His	synonymous_variant	Exon 2 of 2	1	NM_016083.6	ENSP00000358513.2		P21554-1

Frequencies

GnomAD3 genomes

AF:

0.00697

AC:

1060

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00311

AC:

779

AN:

250288

AF XY:

0.00281

show subpopulations

Gnomad AFR exome

AF:

0.0212

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.00757

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00173

AC:

2522

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

1204

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.0215

AC:

719

AN:

33480

American (AMR)

AF:

0.00389

AC:

174

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00735

AC:

192

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00101

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.0234

AC:

135

AN:

5768

European-Non Finnish (NFE)

AF:

0.000859

AC:

955

AN:

1112004

Other (OTH)

AF:

0.00421

AC:

254

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

168

336

503

671

839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00694

AC:

1057

AN:

152264

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

509

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0200

AC:

832

AN:

41538

American (AMR)

AF:

0.00497

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

68020

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00509

Hom.:

Bravo

AF:

0.00864

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00261

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.25

(source)

DANN

Benign

0.45

PhyloP100

-0.81

Mutation Taster

=100/0

polymorphism

(source)

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

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6-88144363-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over