19-40991387-G-GGC

Variant names:

• chr19-40991387-G-GGC
• rs781463375
• NM_000767.5:c.82_83insGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000767.5(CYP2B6):​c.82_83insGC​(p.Asp28GlyfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 152,184 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (17 hom., cov: 31)
  • Exomes 𝑓: 0.00090 (26 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2B6 NM_000767.5 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.31
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-40991387-G-GGC is Benign according to our data. Variant chr19-40991387-G-GGC is described in ClinVar as [Benign]. Clinvar id is 1301545.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00762 (1160/152184) while in subpopulation AFR AF = 0.0268 (1111/41488). AF 95% confidence interval is 0.0255. There are 17 homozygotes in GnomAd4. There are 579 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1160 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2B6	NM_000767.5	c.82_83insGC	p.Asp28GlyfsTer30	frameshift_variant	Exon 1 of 9	ENST00000324071.10	NP_000758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2B6	ENST00000324071.10	c.82_83insGC	p.Asp28GlyfsTer30	frameshift_variant	Exon 1 of 9	1	NM_000767.5	ENSP00000324648.2
CYP2B6	ENST00000598834.2	n.-18_-17insGC		upstream_gene_variant		5		ENSP00000496294.1

Frequencies

GnomAD3 genomes AF: 0.00757 AC: 1151 AN: 152066 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000776 AC: 195 AN: 251356 AF XY: 0.000677

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000900 AC: 1315 AN: 1461754 Hom.: 26 Cov.: 32 AF XY: 0.000800 AC XY: 582 AN XY: 727184

African (AFR) AF: 0.0272 AC: 909 AN: 33392

American (AMR) AF: 0.00105 AC: 47 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000166 AC: 185 AN: 1111986

Other (OTH) AF: 0.00243 AC: 147 AN: 60394

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152184 Hom.: 17 Cov.: 31 AF XY: 0.00778 AC XY: 579 AN XY: 74396

African (AFR) AF: 0.0268 AC: 1111 AN: 41488

American (AMR) AF: 0.00183 AC: 28 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000883 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=162/38	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs781463375; hg19: chr19-41497292;