rs2235018

Variant names:

• chr7-87570049-T-C
• rs2235018
• NM_001348946.2:c.338+123A>G

Variant summary

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

The ENST00000622132.5(ABCB1):​c.338+123A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 882,754 control chromosomes in the GnomAD database, including 1,055 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 0.013 (158 hom., cov: 32)
  • Exomes 𝑓: 0.015 (897 hom.)
• Consequence: ABCB1 ENST00000622132.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.252
• Publications: 2 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000622132.5. 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.338+123A>G		intron	N/A	NP_001335875.1
	ABCB1	NM_001348945.2		c.548+123A>G		intron	N/A	NP_001335874.1
	ABCB1	NM_000927.5		c.338+123A>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.338+123A>G		intron	N/A	ENSP00000478255.1
	ABCB1	ENST00000265724.8	TSL:1	c.338+123A>G		intron	N/A	ENSP00000265724.3
	ABCB1	ENST00000543898.5	TSL:5	c.338+123A>G		intron	N/A	ENSP00000444095.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1971 AN: 152126 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0155 AC: 11317 AN: 730518 Hom.: 897 AF XY: 0.0144 AC XY: 5578 AN XY: 387296

African (AFR) AF: 0.00248 AC: 45 AN: 18176

American (AMR) AF: 0.0649 AC: 2390 AN: 36838

Ashkenazi Jewish (ASJ) AF: 0.00212 AC: 43 AN: 20260

East Asian (EAS) AF: 0.207 AC: 7144 AN: 34522

South Asian (SAS) AF: 0.00766 AC: 498 AN: 64972

European-Finnish (FIN) AF: 0.00601 AC: 243 AN: 40460

Middle Eastern (MID) AF: 0.00186 AC: 7 AN: 3762

European-Non Finnish (NFE) AF: 0.000749 AC: 356 AN: 475282

Other (OTH) AF: 0.0163 AC: 591 AN: 36246

GnomAD4 genome AF: 0.0129 AC: 1969 AN: 152236 Hom.: 158 Cov.: 32 AF XY: 0.0144 AC XY: 1072 AN XY: 74426

African (AFR) AF: 0.00270 AC: 112 AN: 41496

American (AMR) AF: 0.0325 AC: 497 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1140 AN: 5188

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4828

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68034

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00699 Hom.: 7

Bravo AF: 0.0160

Asia WGS AF: 0.102 AC: 353 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.49
PhyloP100		-0.25
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: rs2235018; hg19: chr7-87199365; COSMIC: COSV55950207;