7-87544750-T-C

Variant names:

• chr7-87544750-T-C
• rs2235046
• NM_001348946.2:c.2064+73A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 30 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.2064+73A>G		intron	N/A	NP_001335875.1
	ABCB1	NM_001348945.2		c.2274+73A>G		intron	N/A	NP_001335874.1
	ABCB1	NM_000927.5		c.2064+73A>G		intron	N/A	NP_000918.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.2064+73A>G		intron	N/A	ENSP00000478255.1
	ABCB1	ENST00000265724.8	TSL:1	c.2064+73A>G		intron	N/A	ENSP00000265724.3
	ABCB1	ENST00000543898.5	TSL:5	c.1872+73A>G		intron	N/A	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

African (AFR) AF: 0.760 AC: 23540 AN: 30992

American (AMR) AF: 0.506 AC: 22516 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 15973 AN: 25340

East Asian (EAS) AF: 0.381 AC: 14879 AN: 39086

South Asian (SAS) AF: 0.379 AC: 31721 AN: 83664

European-Finnish (FIN) AF: 0.481 AC: 23417 AN: 48688

Middle Eastern (MID) AF: 0.539 AC: 2984 AN: 5534

European-Non Finnish (NFE) AF: 0.551 AC: 552784 AN: 1004058

Other (OTH) AF: 0.541 AC: 30617 AN: 56564

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

African (AFR) AF: 0.746 AC: 30913 AN: 41454

American (AMR) AF: 0.563 AC: 8585 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2155 AN: 3464

East Asian (EAS) AF: 0.367 AC: 1894 AN: 5158

South Asian (SAS) AF: 0.389 AC: 1876 AN: 4826

European-Finnish (FIN) AF: 0.473 AC: 4993 AN: 10552

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.550 AC: 37372 AN: 67968

Other (OTH) AF: 0.600 AC: 1268 AN: 2112

Alfa AF: 0.559 Hom.: 39044

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

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.77
DANN	Benign	0.32
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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