rs2235035

Positions:

• chr7-87549770-G-A

Variant summary

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

The NM_001348946.2(ABCB1):​c.1554+81C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,494,278 control chromosomes in the GnomAD database, including 74,142 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 0.30 (6809 hom., cov: 32)
  • Exomes 𝑓: 0.31 (67333 hom.)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.0720

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.1554+81C>T		intron_variant		ENST00000622132.5
ABCB1	NM_000927.5	c.1554+81C>T		intron_variant
ABCB1	NM_001348944.2	c.1554+81C>T		intron_variant
ABCB1	NM_001348945.2	c.1764+81C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.1554+81C>T		intron_variant		1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.1554+81C>T		intron_variant		1		P1
ABCB1	ENST00000543898.5	c.1362+81C>T		intron_variant		5
ABCB1	ENST00000482527.1	n.308+81C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44893 AN: 151970 Hom.: 6805 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.313 AC: 419896 AN: 1342190 Hom.: 67333 AF XY: 0.310 AC XY: 209286 AN XY: 674650

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.344

Gnomad4 ASJ exome AF: 0.382

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.295 AC: 44917 AN: 152088 Hom.: 6809 Cov.: 32 AF XY: 0.295 AC XY: 21928 AN XY: 74334

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.383

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.335

Alfa AF: 0.325 Hom.: 11223

Bravo AF: 0.297

Asia WGS AF: 0.240 AC: 835 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	-0.85
CADD	Benign	1.2
DANN	Benign	0.44

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: rs2235035; hg19: chr7-87179086; COSMIC: COSV55951868;