19-40991367-A-T

Variant summary

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

The NM_000767.5(CYP2B6):c.62A>T(p.Gln21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00521 in 1,614,030 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0042 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0053 (28 hom.)
• Consequence: CYP2B6 NM_000767.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.149

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=0.0040751696).
• BP6: Variant 19-40991367-A-T is Benign according to our data. Variant chr19-40991367-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041988.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 641 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.62A>T	p.Gln21Leu	missense_variant	1/9	ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.62A>T	p.Gln21Leu	missense_variant	1/9	1	NM_000767.5	P1
CYP2B6	ENST00000598834.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 641 AN: 152050 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000919

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00418 AC: 1052 AN: 251442 Hom.: 4 AF XY: 0.00432 AC XY: 587 AN XY: 135896

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00532 AC: 7775 AN: 1461864 Hom.: 28 Cov.: 31 AF XY: 0.00523 AC XY: 3805 AN XY: 727232

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00610

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.00421 AC: 641 AN: 152166 Hom.: 3 Cov.: 31 AF XY: 0.00390 AC XY: 290 AN XY: 74388

Gnomad4 AFR AF: 0.000916

Gnomad4 AMR AF: 0.00955

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00571

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00591 Hom.: 0

Bravo AF: 0.00458

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00385 AC: 468

EpiCase AF: 0.00747

EpiControl AF: 0.00907

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CYP2B6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.31
Dann	Benign	0.79
DEOGEN2	Benign	0.0084	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
Polyphen		0.011	B;B
Vest4		0.19
MVP		0.37
MPC		0.067
ClinPred		0.0027	T
GERP RS		-4.5
Varity_R		0.049
gMVP		0.36

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: rs34883432; hg19: chr19-41497272;