7-87544750-T-C

Position:

• chr7-87544750-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348946.2(ABCB1):​c.2064+73A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,490,404 control chromosomes in the GnomAD database, including 223,288 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 0.59 (27428 hom., cov: 32)
  • Exomes 𝑓: 0.54 (195860 hom.)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.44

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.2064+73A>G		intron_variant		ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.2274+73A>G		intron_variant			NP_001335874.1
ABCB1	NM_000927.5	c.2064+73A>G		intron_variant			NP_000918.2
ABCB1	NM_001348944.2	c.2064+73A>G		intron_variant			NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.2064+73A>G		intron_variant		1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.2064+73A>G		intron_variant		1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.1872+73A>G		intron_variant		5		ENSP00000444095.1

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89707 AN: 151880 Hom.: 27380 Cov.: 32

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.602

GnomAD4 exome AF: 0.537 AC: 718431 AN: 1338408 Hom.: 195860 AF XY: 0.531 AC XY: 357139 AN XY: 672502

Gnomad4 AFR exome AF: 0.760

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.630

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.379

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.541

GnomAD4 genome AF: 0.591 AC: 89824 AN: 151996 Hom.: 27428 Cov.: 32 AF XY: 0.583 AC XY: 43318 AN XY: 74268

Gnomad4 AFR AF: 0.746

Gnomad4 AMR AF: 0.563

Gnomad4 ASJ AF: 0.622

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.550

Gnomad4 OTH AF: 0.600

Alfa AF: 0.552 Hom.: 29780

Bravo AF: 0.605

Asia WGS AF: 0.417 AC: 1454 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	-0.96
CADD	Benign	0.77
DANN	Benign	0.32

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: rs2235046; hg19: chr7-87174066; COSMIC: COSV55944832; COSMIC: COSV55944832;