19-41008518-T-C

Variant names:

• chr19-41008518-T-C
• rs10401737
• NM_000767.5:c.646-701T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000767.5(CYP2B6):​c.646-701T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 118,594 control chromosomes in the GnomAD database, including 2,364 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2364 hom., cov: 23)
• Consequence: CYP2B6 NM_000767.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.86
• Publications: 3 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.646-701T>C		intron_variant	Intron 4 of 8	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.646-701T>C		intron_variant	Intron 4 of 8	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000593831.1	c.257-3780T>C		intron_variant	Intron 2 of 4	2		ENSP00000470582.1
CYP2B6	ENST00000598834.2	n.*87-701T>C		intron_variant	Intron 5 of 9	5		ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 22402 AN: 118488 Hom.: 2362 Cov.: 23

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.199

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.189 AC: 22420 AN: 118594 Hom.: 2364 Cov.: 23 AF XY: 0.185 AC XY: 10632 AN XY: 57622

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

African (AFR) AF: 0.263 AC: 7551 AN: 28702

American (AMR) AF: 0.221 AC: 2512 AN: 11364

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 529 AN: 2810

East Asian (EAS) AF: 0.131 AC: 579 AN: 4408

South Asian (SAS) AF: 0.221 AC: 708 AN: 3208

European-Finnish (FIN) AF: 0.115 AC: 1039 AN: 8998

Middle Eastern (MID) AF: 0.234 AC: 59 AN: 252

European-Non Finnish (NFE) AF: 0.161 AC: 9055 AN: 56376

Other (OTH) AF: 0.203 AC: 329 AN: 1624

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.218 Hom.: 1215

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.48
DANN	Benign	0.38
PhyloP100		-4.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10401737; hg19: chr19-41514423; COSMIC: COSV57844671; COSMIC: COSV57844671;