19-41006966-C-T

Variant names:

• chr19-41006966-C-T
• rs45459594
• NM_000767.5:c.546C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_000767.5(CYP2B6):​c.546C>T​(p.Ile182Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CYP2B6 NM_000767.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.56
• Publications: 6 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=-3.56 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000767.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2B6	NM_000767.5	MANE Select	c.546C>T	p.Ile182Ile	synonymous	Exon 4 of 9	NP_000758.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2B6	ENST00000324071.10	TSL:1 MANE Select	c.546C>T	p.Ile182Ile	synonymous	Exon 4 of 9	ENSP00000324648.2
	CYP2B6	ENST00000594187.1	TSL:5	n.130C>T		non_coding_transcript_exon	Exon 2 of 2
	CYP2B6	ENST00000598834.2	TSL:5	n.447C>T		non_coding_transcript_exon	Exon 4 of 10	ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251320 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461700 Hom.: 0 Cov.: 33 AF XY: 0.000103 AC XY: 75 AN XY: 727156

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

African (AFR) AF: 0.00246 AC: 82 AN: 33346

American (AMR) AF: 0.000447 AC: 20 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111986

Other (OTH) AF: 0.000282 AC: 17 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.00130 AC XY: 97 AN XY: 74394

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

African (AFR) AF: 0.00420 AC: 174 AN: 41432

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ 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: 0.0000443 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.7
DANN	Benign	0.60
PhyloP100		-3.6

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

Other links and lift over

dbSNP: rs45459594; hg19: chr19-41512871; COSMIC: COSV104636387; COSMIC: COSV104636387;