7-87595632-C-G

Variant names:

• chr7-87595632-C-G
• rs2214103
• NM_001348946.2:c.117+134G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 4554 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.117+134G>C		intron	N/A	NP_001335875.1	P08183-1
	ABCB1	NM_001348945.2		c.327+134G>C		intron	N/A	NP_001335874.1
	ABCB1	NM_000927.5		c.117+134G>C		intron	N/A	NP_000918.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.117+134G>C		intron	N/A	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.117+134G>C		intron	N/A	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000890305.1		c.117+134G>C		intron	N/A	ENSP00000560364.1

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

African (AFR) AF: 0.0178 AC: 261 AN: 14694

American (AMR) AF: 0.0232 AC: 591 AN: 25444

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 412 AN: 16640

East Asian (EAS) AF: 0.0000928 AC: 3 AN: 32326

South Asian (SAS) AF: 0.0238 AC: 1249 AN: 52526

European-Finnish (FIN) AF: 0.0366 AC: 1622 AN: 44342

Middle Eastern (MID) AF: 0.0399 AC: 120 AN: 3004

European-Non Finnish (NFE) AF: 0.0396 AC: 13545 AN: 342200

Other (OTH) AF: 0.0331 AC: 980 AN: 29594

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

African (AFR) AF: 0.0208 AC: 865 AN: 41548

American (AMR) AF: 0.0209 AC: 320 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 75 AN: 3462

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4822

European-Finnish (FIN) AF: 0.0339 AC: 359 AN: 10598

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2691 AN: 67904

Other (OTH) AF: 0.0379 AC: 80 AN: 2110

Alfa AF: 0.0355 Hom.: 12

Bravo AF: 0.0286

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

ClinVar submissions

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	-0.84
CADD	Benign	2.7
DANN	Benign	0.60
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism

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: rs2214103; hg19: chr7-87224948;