7-87595632-C-G

Position:

• chr7-87595632-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001348946.2(ABCB1):​c.117+134G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 712,888 control chromosomes in the GnomAD database, including 437 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 0.030 (63 hom., cov: 32)
  • Exomes 𝑓: 0.033 (374 hom.)
• Consequence: ABCB1 NM_001348946.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.103

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0299 (4554/152118) while in subpopulation NFE AF= 0.0396 (2691/67904). AF 95% confidence interval is 0.0384. There are 63 homozygotes in gnomad4. There are 2172 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 4554 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.117+134G>C		intron_variant		ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.327+134G>C		intron_variant			NP_001335874.1
ABCB1	NM_000927.5	c.117+134G>C		intron_variant			NP_000918.2
ABCB1	NM_001348944.2	c.117+134G>C		intron_variant			NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.117+134G>C		intron_variant		1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.117+134G>C		intron_variant		1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.117+134G>C		intron_variant		5		ENSP00000444095.1
ABCB1	ENST00000416177.1	c.117+134G>C		intron_variant		5		ENSP00000399419.1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4549 AN: 152000 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0217

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.0335 AC: 18783 AN: 560770 Hom.: 374 AF XY: 0.0333 AC XY: 9918 AN XY: 298132

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0248

Gnomad4 EAS exome AF: 0.0000928

Gnomad4 SAS exome AF: 0.0238

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0396

Gnomad4 OTH exome AF: 0.0331

GnomAD4 genome AF: 0.0299 AC: 4554 AN: 152118 Hom.: 63 Cov.: 32 AF XY: 0.0292 AC XY: 2172 AN XY: 74374

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.0217

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.0396

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0355 Hom.: 12

Bravo AF: 0.0286

Asia WGS AF: 0.0190 AC: 67 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	-0.84
CADD	Benign	2.7
DANN	Benign	0.60

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: rs2214103; hg19: chr7-87224948;