rs2235015

Positions:

• chr7-87570248-C-A
• chr7-87570248-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001348946.2(ABCB1):​c.287-25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,594,280 control chromosomes in the GnomAD database, including 31,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4369 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27471 hom.)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -1.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-87570248-C-A is Benign according to our data. Variant chr7-87570248-C-A is described in ClinVar as [Benign]. Clinvar id is 675797.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.287-25G>T		intron_variant		ENST00000622132.5
ABCB1	NM_000927.5	c.287-25G>T		intron_variant
ABCB1	NM_001348944.2	c.287-25G>T		intron_variant
ABCB1	NM_001348945.2	c.497-25G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.287-25G>T		intron_variant		1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.287-25G>T		intron_variant		1		P1
ABCB1	ENST00000543898.5	c.287-25G>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34097 AN: 151940 Hom.: 4361 Cov.: 33

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.213

GnomAD3 exomes AF: 0.178 AC: 44574 AN: 250346 Hom.: 4581 AF XY: 0.176 AC XY: 23812 AN XY: 135404

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.0580

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.189 AC: 273207 AN: 1442222 Hom.: 27471 Cov.: 28 AF XY: 0.188 AC XY: 135176 AN XY: 718684

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.0550

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.225 AC: 34154 AN: 152058 Hom.: 4369 Cov.: 33 AF XY: 0.221 AC XY: 16407 AN XY: 74336

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0595

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.216

Alfa AF: 0.190 Hom.: 3419

Bravo AF: 0.231

Asia WGS AF: 0.141 AC: 491 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	-0.81
CADD	Benign	0.72
DANN	Benign	0.73

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: rs2235015; hg19: chr7-87199564;