rs35449271

chr19-41012668-C-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.1153-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,613,298 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (43 hom.)
• Consequence: CYP2B6 NM_000767.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004234
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.558

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 (BayesDel_noAF=-0.81).
• BP6: Variant 19-41012668-C-T is Benign according to our data. Variant chr19-41012668-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3024890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 779 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2B6	NM_000767.5	c.1153-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000324071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2B6	ENST00000324071.10	c.1153-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000767.5	P1
CYP2B6	ENST00000597612.1	n.647+183C>T		intron_variant, non_coding_transcript_variant		1
CYP2B6	ENST00000593831.1	c.445-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
CYP2B6	ENST00000598834.2	c.*593+183C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 779 AN: 151832 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00535 AC: 1344 AN: 251230 Hom.: 5 AF XY: 0.00554 AC XY: 752 AN XY: 135792

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.00670

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00513 AC: 7493 AN: 1461350 Hom.: 43 Cov.: 32 AF XY: 0.00508 AC XY: 3696 AN XY: 726976

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.00540

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00512 AC: 778 AN: 151948 Hom.: 5 Cov.: 32 AF XY: 0.00534 AC XY: 397 AN XY: 74276

Gnomad4 AFR AF: 0.00218

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.00640

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00557 Hom.: 1

EpiCase AF: 0.00747

EpiControl AF: 0.00539

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

CYP2B6: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.4
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.030		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: rs35449271; hg19: chr19-41518573;