chr19-41012693-T-A

Position:

• chr19-41012693-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000324071.10(CYP2B6):​c.1172T>A​(p.Ile391Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,614,074 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (70 hom.)
• Consequence: CYP2B6 ENST00000324071.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016278386).
• BS2: High AC in GnomAd4 at 728 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.1172T>A	p.Ile391Asn	missense_variant	8/9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.1172T>A	p.Ile391Asn	missense_variant	8/9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000597612.1	n.647+208T>A		intron_variant		1
CYP2B6	ENST00000593831.1	c.464T>A	p.Ile155Asn	missense_variant	4/5	2		ENSP00000470582.1
CYP2B6	ENST00000598834.2	n.*593+208T>A		intron_variant		5		ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 728 AN: 152144 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00842

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00437 AC: 1098 AN: 251386 Hom.: 4 AF XY: 0.00434 AC XY: 590 AN XY: 135870

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00814

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00782 AC: 11428 AN: 1461812 Hom.: 70 Cov.: 32 AF XY: 0.00752 AC XY: 5468 AN XY: 727208

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.00974

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152262 Hom.: 4 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74444

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00842

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00616 Hom.: 1

Bravo AF: 0.00480

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00458 AC: 556

EpiCase AF: 0.00758

EpiControl AF: 0.00741

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.045	T;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.085	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.2	.;D;.
REVEL	Benign	0.11
Sift	Uncertain	0.0060	.;D;.
Sift4G	Uncertain	0.045	.;D;T
Polyphen		0.99	D;D;.
Vest4		0.47, 0.48
MVP		0.39
MPC		0.21
ClinPred		0.038	T
GERP RS		3.9
Varity_R		0.81
gMVP		0.32

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: rs35979566; hg19: chr19-41518598;