7-87600185-T-C

Position:

• chr7-87600185-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001348945.2(ABCB1):​c.210A>G​(p.Gly70Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 1,613,460 control chromosomes in the GnomAD database, including 695,992 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 0.95 (68389 hom., cov: 32)
  • Exomes 𝑓: 0.93 (627603 hom.)
• Consequence: ABCB1 NM_001348945.2 synonymous
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.73

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.-1A>G		5_prime_UTR_variant	2/28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.210A>G	p.Gly70Gly	synonymous_variant	6/32		NP_001335874.1
ABCB1	NM_000927.5	c.-1A>G		5_prime_UTR_variant	3/29		NP_000918.2
ABCB1	NM_001348944.2	c.-1A>G		5_prime_UTR_variant	4/30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.-1A>G		5_prime_UTR_variant	2/28	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.-1A>G		5_prime_UTR_variant	3/29	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.-1A>G		5_prime_UTR_variant	3/28	5		ENSP00000444095.1
ABCB1	ENST00000416177.1	c.-1A>G		5_prime_UTR_variant	4/6	5		ENSP00000399419.1

Frequencies

GnomAD3 genomes AF: 0.947 AC: 144120 AN: 152202 Hom.: 68324 Cov.: 32

Gnomad AFR AF: 0.985

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.972

Gnomad ASJ AF: 0.965

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.952

GnomAD3 exomes AF: 0.946 AC: 237728 AN: 251178 Hom.: 112667 AF XY: 0.946 AC XY: 128448 AN XY: 135754

Gnomad AFR exome AF: 0.986

Gnomad AMR exome AF: 0.977

Gnomad ASJ exome AF: 0.966

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.988

Gnomad FIN exome AF: 0.910

Gnomad NFE exome AF: 0.917

Gnomad OTH exome AF: 0.946

GnomAD4 exome AF: 0.926 AC: 1353616 AN: 1461140 Hom.: 627603 Cov.: 46 AF XY: 0.929 AC XY: 674929 AN XY: 726886

Gnomad4 AFR exome AF: 0.988

Gnomad4 AMR exome AF: 0.976

Gnomad4 ASJ exome AF: 0.967

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.988

Gnomad4 FIN exome AF: 0.908

Gnomad4 NFE exome AF: 0.914

Gnomad4 OTH exome AF: 0.940

GnomAD4 genome AF: 0.947 AC: 144244 AN: 152320 Hom.: 68389 Cov.: 32 AF XY: 0.950 AC XY: 70749 AN XY: 74488

Gnomad4 AFR AF: 0.985

Gnomad4 AMR AF: 0.972

Gnomad4 ASJ AF: 0.965

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.991

Gnomad4 FIN AF: 0.909

Gnomad4 NFE AF: 0.917

Gnomad4 OTH AF: 0.952

Alfa AF: 0.928 Hom.: 154967

Bravo AF: 0.953

Asia WGS AF: 0.992 AC: 3449 AN: 3478

EpiCase AF: 0.925

EpiControl AF: 0.924

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	-0.76
CADD	Benign	7.0
DANN	Benign	0.56

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: rs2214102; hg19: chr7-87229501;