Genetic Variant CYP2B6:p.Ala102Thr (chr19-41004133-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000767.5(CYP2B6):c.304G>A(p.Ala102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,543,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A102S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000022 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CYP2B6
NM_000767.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.380

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25404254).

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5 link	c.304G>A	p.Ala102Thr	missense_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.304G>A	p.Ala102Thr	missense_variant	Exon 2 of 9	1	NM_000767.5	ENSP00000324648.2	P20813-1
CYP2B6	ENST00000593831.1 link	c.76G>A	p.Ala26Thr	missense_variant	Exon 1 of 5	2		ENSP00000470582.1	M0QZJ2
CYP2B6	ENST00000598834.2 link	n.205G>A		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000496294.1	A0A2R8YFA4
CYP2B6	ENST00000594187.1 link	n.-246G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000216

AC:

AN:

138874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000267

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:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251264

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1404986

Hom.:

Cov.:

AF XY:

0.0000258

AC XY:

AN XY:

698688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31830

American (AMR)

AF:

0.00

AC:

AN:

43100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24126

East Asian (EAS)

AF:

0.0000292

AC:

AN:

34276

South Asian (SAS)

AF:

0.0000699

AC:

AN:

85816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5508

European-Non Finnish (NFE)

AF:

0.0000158

AC:

AN:

1075676

Other (OTH)

AF:

0.0000529

AC:

AN:

56672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000216

AC:

AN:

138874

Hom.:

Cov.:

AF XY:

0.0000450

AC XY:

AN XY:

66632

show subpopulations

African (AFR)

AF:

0.0000267

AC:

AN:

37484

American (AMR)

AF:

0.00

AC:

AN:

12458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4376

South Asian (SAS)

AF:

0.00

AC:

AN:

4146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65768

Other (OTH)

AF:

0.00

AC:

AN:

1926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.63

.;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

0.38

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

.;N;.

REVEL

Benign

0.17

Sift

Uncertain

0.019

.;D;.

Sift4G

Uncertain

0.039

.;D;D

Polyphen

0.99

D;D;.

Vest4

0.26

MutPred

0.69

Loss of stability (P = 0.1037);Loss of stability (P = 0.1037);.;

MVP

0.81

MPC

0.13

ClinPred

0.097

GERP RS

-0.97

PromoterAI

-0.039

Neutral

(source)

Varity_R

0.65

gMVP

0.30

Mutation Taster

=86/14

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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chr19-41004133-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over