rs35773040

Positions:

• chr19-41004381-G-A
• chr19-41004381-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000324071.10(CYP2B6):​c.419G>A​(p.Arg140Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,613,998 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (17 hom.)
• Consequence: CYP2B6 ENST00000324071.10 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068762302).
• BP6: Variant 19-41004381-G-A is Benign according to our data. Variant chr19-41004381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2649918.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.419G>A	p.Arg140Gln	missense_variant	3/9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.419G>A	p.Arg140Gln	missense_variant	3/9	1	NM_000767.5	ENSP00000324648	P1
CYP2B6	ENST00000593831.1	c.191G>A	p.Arg64Gln	missense_variant	2/5	2		ENSP00000470582
CYP2B6	ENST00000594187.1	n.3G>A		non_coding_transcript_exon_variant	1/2	5
CYP2B6	ENST00000598834.2	c.323G>A	p.Arg108Gln	missense_variant, NMD_transcript_variant	3/10	5		ENSP00000496294

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 152076 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00314 AC: 789 AN: 251270 Hom.: 4 AF XY: 0.00335 AC XY: 455 AN XY: 135800

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.00555

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00326 AC: 4761 AN: 1461804 Hom.: 17 Cov.: 33 AF XY: 0.00332 AC XY: 2416 AN XY: 727202

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152194 Hom.: 1 Cov.: 31 AF XY: 0.00329 AC XY: 245 AN XY: 74422

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00361 Hom.: 2

Bravo AF: 0.00226

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00343 AC: 416

EpiCase AF: 0.00294

EpiControl AF: 0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

CYP2B6: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	.;N;.
REVEL	Benign	0.069
Sift	Benign	0.052	.;T;.
Sift4G	Benign	0.085	.;T;D
Polyphen		0.020	B;B;.
Vest4		0.22, 0.23
MVP		0.39
MPC		0.079
ClinPred		0.030	T
GERP RS		1.7
Varity_R		0.36
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs35773040; hg19: chr19-41510286; COSMIC: COSV105887593;