rs2888599

Positions:

• chr7-87599709-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001348946.2(ABCB1):​c.68+408G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 152,234 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency: Genomes: 𝑓 0.030 (64 hom., cov: 32)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.72

Genes affected

ABCB1 (HGNC:40): (ATP binding cassette subfamily B member 1) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.03 (4565/152234) while in subpopulation NFE AF= 0.0397 (2699/68024). AF 95% confidence interval is 0.0384. There are 64 homozygotes in gnomad4. There are 2181 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 4565 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.68+408G>A		intron_variant		ENST00000622132.5
ABCB1	NM_000927.5	c.68+408G>A		intron_variant
ABCB1	NM_001348944.2	c.68+408G>A		intron_variant
ABCB1	NM_001348945.2	c.278+408G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.68+408G>A		intron_variant		1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.68+408G>A		intron_variant		1		P1
ABCB1	ENST00000416177.1	c.68+408G>A		intron_variant		5
ABCB1	ENST00000543898.5	c.68+408G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4558 AN: 152116 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0283

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0392

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

GnomAD4 genome AF: 0.0300 AC: 4565 AN: 152234 Hom.: 64 Cov.: 32 AF XY: 0.0293 AC XY: 2181 AN XY: 74420

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0283

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0355 Hom.: 12

Bravo AF: 0.0286

Asia WGS AF: 0.0200 AC: 73 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs2888599; hg19: chr7-87229025;