rs2888599

Variant names:

• chr7-87599709-C-T
• rs2888599
• NM_001348946.2:c.68+408G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4565 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348946.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.68+408G>A		intron	N/A	NP_001335875.1	P08183-1
	ABCB1	NM_001348945.2		c.278+408G>A		intron	N/A	NP_001335874.1
	ABCB1	NM_000927.5		c.68+408G>A		intron	N/A	NP_000918.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.68+408G>A		intron	N/A	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.68+408G>A		intron	N/A	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000890305.1		c.68+408G>A		intron	N/A	ENSP00000560364.1

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

African (AFR) AF: 0.0204 AC: 849 AN: 41542

American (AMR) AF: 0.0220 AC: 337 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.0283 AC: 136 AN: 4804

European-Finnish (FIN) AF: 0.0342 AC: 362 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2699 AN: 68024

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0346 Hom.: 12

Bravo AF: 0.0286

Asia WGS AF: 0.0200 AC: 73 AN: 3478

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

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: rs2888599; hg19: chr7-87229025;