rs34223104

Variant names:

• chr19-40991224-T-C
• rs34223104
• NM_000767.5:c.-82T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_000767.5(CYP2B6):​c.-82T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,487,700 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (44 hom., cov: 31)
  • Exomes 𝑓: 0.010 (130 hom.)
• Consequence: CYP2B6 NM_000767.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119

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 Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 19-40991224-T-C is Pathogenic according to our data. Variant chr19-40991224-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0162 (2469/152140) while in subpopulation AFR AF= 0.0295 (1221/41456). AF 95% confidence interval is 0.0281. There are 44 homozygotes in gnomad4. There are 1216 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.-82T>C		upstream_gene_variant		ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.-82T>C		upstream_gene_variant		1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000598834.2	n.-181T>C		upstream_gene_variant		5		ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2461 AN: 152022 Hom.: 45 Cov.: 31

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.00707

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0104 AC: 13856 AN: 1335560 Hom.: 130 Cov.: 20 AF XY: 0.0107 AC XY: 7188 AN XY: 670682

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00948

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.00755

Gnomad4 NFE exome AF: 0.00928

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0162 AC: 2469 AN: 152140 Hom.: 44 Cov.: 31 AF XY: 0.0164 AC XY: 1216 AN XY: 74368

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.00707

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0135 Hom.: 3

Bravo AF: 0.0172

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	12
DANN	Benign	0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34223104; hg19: chr19-41497129;