19-41004161-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000767.5(CYP2B6):c.332A>G(p.Tyr111Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 958,204 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CYP2B6
NM_000767.5 missense, splice_region

Scores

Splicing: ADA: 0.005061

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.943

Publications

2 publications found

Variant links:

Genes affected

CYP2B6 (HGNC:2615): (cytochrome P450 family 2 subfamily B member 6) This gene, CYP2B6, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by phenobarbital. The enzyme is known to metabolize some xenobiotics, such as the anti-cancer drugs cyclophosphamide and ifosphamide. Transcript variants for this gene have been described; however, it has not been resolved whether these transcripts are in fact produced by this gene or by a closely related pseudogene, CYP2B7. Both the gene and the pseudogene are located in the middle of a CYP2A pseudogene found in a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]

CYP2B6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000324071.10	NP_000758.1	P20813-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2B6	ENST00000324071.10 link	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_000767.5	ENSP00000324648.2	P20813-1
CYP2B6	ENST00000593831.1 link	c.104A>G	p.Tyr35Cys	missense_variant, splice_region_variant	Exon 1 of 5	2		ENSP00000470582.1	M0QZJ2
CYP2B6	ENST00000598834.2 link	n.233A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000496294.1	A0A2R8YFA4
CYP2B6	ENST00000594187.1 link	n.-218A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000184

AC:

AN:

108522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000171

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250682

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

849682

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

430934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19640

American (AMR)

AF:

0.00

AC:

AN:

37012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14948

East Asian (EAS)

AF:

0.00

AC:

AN:

15796

South Asian (SAS)

AF:

0.00

AC:

AN:

76176

European-Finnish (FIN)

AF:

0.0000305

AC:

AN:

32818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3750

European-Non Finnish (NFE)

AF:

0.0000470

AC:

AN:

617480

Other (OTH)

AF:

0.0000312

AC:

AN:

32062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000184

AC:

AN:

108522

Hom.:

Cov.:

AF XY:

0.0000203

AC XY:

AN XY:

49218

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000360

AC:

AN:

27756

American (AMR)

AF:

0.00

AC:

AN:

6990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3100

East Asian (EAS)

AF:

0.00

AC:

AN:

3250

South Asian (SAS)

AF:

0.00

AC:

AN:

2972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

58546

Other (OTH)

AF:

0.00

AC:

AN:

1444

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000740

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.332A>G (p.Y111C) alteration is located in exon 2 (coding exon 2) of the CYP2B6 gene. This alteration results from a A to G substitution at nucleotide position 332, causing the tyrosine (Y) at amino acid position 111 to be replaced by a cysteine (C). 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

0.18

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.043

T;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.32

.;T;T

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.4

M;M;.

PhyloP100

0.94

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.0

.;D;.

REVEL

Benign

0.24

Sift

Benign

0.030

.;D;.

Sift4G

Benign

0.070

.;T;T

Polyphen

1.0

D;D;.

Vest4

0.47, 0.46

MVP

0.84

MPC

0.40

ClinPred

0.65

GERP RS

0.048

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.48

gMVP

0.43

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0051

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-41004161-A-G

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