rs2032582

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001348946.2(ABCB1):c.2677T>G(p.Ser893Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,611,172 control chromosomes in the GnomAD database, including 250,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 33550 hom., cov: 32)

Exomes 𝑓: 0.54 ( 217160 hom. )

Consequence

ABCB1
NM_001348946.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 2.22

Variant links:

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]

ABCB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.965592E-7).

BP6

Variant 7-87531302-A-C is Benign according to our data. Variant chr7-87531302-A-C is described in ClinVar as [Benign]. Clinvar id is 166622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87531302-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCB1	NM_001348946.2 linkuse as main transcript	c.2677T>G	p.Ser893Ala	missense_variant	21/28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2 linkuse as main transcript	c.2887T>G	p.Ser963Ala	missense_variant	25/32		NP_001335874.1
ABCB1	NM_000927.5 linkuse as main transcript	c.2677T>G	p.Ser893Ala	missense_variant	22/29		NP_000918.2
ABCB1	NM_001348944.2 linkuse as main transcript	c.2677T>G	p.Ser893Ala	missense_variant	23/30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5 linkuse as main transcript	c.2677T>G	p.Ser893Ala	missense_variant	21/28	1	NM_001348946.2	ENSP00000478255	P1	P08183-1

Frequencies

GnomAD3 genomes

AF:

0.641

AC:

97433

AN:

151960

Hom.:

33483

Cov.:

show subpopulations

Gnomad AFR

AF:

0.910

Gnomad AMI

AF:

0.599

Gnomad AMR

AF:

0.603

Gnomad ASJ

AF:

0.628

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.355

Gnomad FIN

AF:

0.476

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.546

Gnomad OTH

AF:

0.647

GnomAD3 exomes

AF:

0.539

AC:

135082

AN:

250640

Hom.:

38434

AF XY:

0.524

AC XY:

70967

AN XY:

135446

show subpopulations

Gnomad AFR exome

AF:

0.918

Gnomad AMR exome

AF:

0.548

Gnomad ASJ exome

AF:

0.624

Gnomad EAS exome

AF:

0.475

Gnomad SAS exome

AF:

0.349

Gnomad FIN exome

AF:

0.469

Gnomad NFE exome

AF:

0.549

Gnomad OTH exome

AF:

0.548

GnomAD4 exome

AF:

0.539

AC:

786633

AN:

1459094

Hom.:

217160

Cov.:

AF XY:

0.532

AC XY:

386422

AN XY:

725932

show subpopulations

Gnomad4 AFR exome

AF:

0.926

Gnomad4 AMR exome

AF:

0.549

Gnomad4 ASJ exome

AF:

0.633

Gnomad4 EAS exome

AF:

0.442

Gnomad4 SAS exome

AF:

0.350

Gnomad4 FIN exome

AF:

0.475

Gnomad4 NFE exome

AF:

0.545

Gnomad4 OTH exome

AF:

0.557

GnomAD4 genome

AF:

0.642

AC:

97571

AN:

152078

Hom.:

33550

Cov.:

AF XY:

0.634

AC XY:

47095

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.911

Gnomad4 AMR

AF:

0.604

Gnomad4 ASJ

AF:

0.628

Gnomad4 EAS

AF:

0.474

Gnomad4 SAS

AF:

0.358

Gnomad4 FIN

AF:

0.476

Gnomad4 NFE

AF:

0.546

Gnomad4 OTH

AF:

0.643

Alfa

AF:

0.555

Hom.:

42212

Bravo

AF:

0.679

TwinsUK

AF:

0.551

AC:

2042

ALSPAC

AF:

0.554

AC:

2136

ESP6500AA

AF:

0.892

AC:

3930

ESP6500EA

AF:

0.568

AC:

4889

ExAC

AF:

0.543

AC:

65897

EpiCase

AF:

0.543

EpiControl

AF:

0.545

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 27, 2014

- -

ABCB1-related disorder

Benign:1

Likely benign, no assertion criteria provided

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). -

Inflammatory bowel disease 13

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

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

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.33

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.23

T;.;T

MetaRNN

Benign

0.0000010

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.0

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

1.7

.;N;N

REVEL

Benign

0.28

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.043

MPC

0.17

ClinPred

0.0027

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over