rs1128503

chr7-87550285-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001348946.2(ABCB1):c.1236T>C(p.Gly412=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,613,758 control chromosomes in the GnomAD database, including 256,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30325 hom., cov: 32)
  • Exomes 𝑓: 0.55 (226668 hom.)
• Consequence: ABCB1 NM_001348946.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.153

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-87550285-A-G is Benign according to our data. Variant chr7-87550285-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 194187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87550285-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.1236T>C	p.Gly412=	synonymous_variant	12/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.1446T>C	p.Gly482=	synonymous_variant	16/32
ABCB1	NM_000927.5	c.1236T>C	p.Gly412=	synonymous_variant	13/29
ABCB1	NM_001348944.2	c.1236T>C	p.Gly412=	synonymous_variant	14/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.1236T>C	p.Gly412=	synonymous_variant	12/28	1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.1236T>C	p.Gly412=	synonymous_variant	13/29	1		P1
ABCB1	ENST00000543898.5	c.1044T>C	p.Gly348=	synonymous_variant	12/28	5

Frequencies

GnomAD3 genomes AF: 0.619 AC: 93943 AN: 151856 Hom.: 30269 Cov.: 32

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.537 AC: 134826 AN: 251258 Hom.: 37666 AF XY: 0.527 AC XY: 71570 AN XY: 135790

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.357

Gnomad SAS exome AF: 0.393

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.553 AC: 807661 AN: 1461784 Hom.: 226668 Cov.: 68 AF XY: 0.547 AC XY: 397991 AN XY: 727196

Gnomad4 AFR exome AF: 0.822

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.643

Gnomad4 EAS exome AF: 0.376

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.564

Gnomad4 OTH exome AF: 0.556

GnomAD4 genome AF: 0.619 AC: 94069 AN: 151974 Hom.: 30325 Cov.: 32 AF XY: 0.612 AC XY: 45432 AN XY: 74252

Gnomad4 AFR AF: 0.807

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.634

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.401

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.564

Gnomad4 OTH AF: 0.619

Alfa AF: 0.577 Hom.: 54035

Bravo AF: 0.632

Asia WGS AF: 0.429 AC: 1498 AN: 3478

EpiCase AF: 0.561

EpiControl AF: 0.563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 06, 2014

- -

ABCB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	-0.62
CADD	Benign	2.3
DANN	Benign	0.45

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: rs1128503; hg19: chr7-87179601; COSMIC: COSV55946864; COSMIC: COSV55946864;