rs2032588

Variant names:

• chr7-87550127-G-A
• rs2032588
• NM_001348946.2:c.1350+44C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348946.2(ABCB1):​c.1350+44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,930 control chromosomes in the GnomAD database, including 4,242 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 0.094 (1001 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3241 hom.)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.336
• Publications: 25 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.1350+44C>T		intron_variant	Intron 12 of 27	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.1560+44C>T		intron_variant	Intron 16 of 31		NP_001335874.1
ABCB1	NM_000927.5	c.1350+44C>T		intron_variant	Intron 13 of 28		NP_000918.2
ABCB1	NM_001348944.2	c.1350+44C>T		intron_variant	Intron 14 of 29		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.1350+44C>T		intron_variant	Intron 12 of 27	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.1350+44C>T		intron_variant	Intron 13 of 28	1		ENSP00000265724.3
ABCB1	ENST00000482527.1	n.32C>T		non_coding_transcript_exon_variant	Exon 1 of 3	4
ABCB1	ENST00000543898.5	c.1158+44C>T		intron_variant	Intron 12 of 27	5		ENSP00000444095.1

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14256 AN: 152116 Hom.: 996 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0498

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0953

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0813

GnomAD2 exomes AF: 0.0555 AC: 13956 AN: 251310 AF XY: 0.0517

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.0630

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0579

Gnomad OTH exome AF: 0.0581

GnomAD4 exome AF: 0.0584 AC: 85421 AN: 1461696 Hom.: 3241 Cov.: 54 AF XY: 0.0563 AC XY: 40915 AN XY: 727172

African (AFR) AF: 0.209 AC: 6998 AN: 33476

American (AMR) AF: 0.0319 AC: 1425 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 1666 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00582 AC: 502 AN: 86250

European-Finnish (FIN) AF: 0.0913 AC: 4868 AN: 53294

Middle Eastern (MID) AF: 0.0728 AC: 420 AN: 5768

European-Non Finnish (NFE) AF: 0.0591 AC: 65767 AN: 1111958

Other (OTH) AF: 0.0625 AC: 3773 AN: 60392

GnomAD4 genome AF: 0.0939 AC: 14290 AN: 152234 Hom.: 1001 Cov.: 33 AF XY: 0.0922 AC XY: 6863 AN XY: 74446

African (AFR) AF: 0.194 AC: 8049 AN: 41532

American (AMR) AF: 0.0496 AC: 759 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.0953 AC: 1010 AN: 10596

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0586 AC: 3988 AN: 68012

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0674 Hom.: 877

Bravo AF: 0.0965

Asia WGS AF: 0.0200 AC: 73 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.44
DANN	Benign	0.54
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2032588; hg19: chr7-87179443;