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rs2032582

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S893Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.64 ( 33550 hom., cov: 32)
Exomes 𝑓: 0.54 ( 217160 hom. )

Consequence

ABCB1
NM_001348946.2 missense

Scores

14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O: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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-87531301-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1164001.Status of the report is no_assertion_criteria_provided, 0 stars.
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 [Likely_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 UniProt
ABCB1NM_001348946.2 linkuse as main transcriptc.2677T>G p.Ser893Ala missense_variant 21/28 ENST00000622132.5
ABCB1NM_001348945.2 linkuse as main transcriptc.2887T>G p.Ser963Ala missense_variant 25/32
ABCB1NM_000927.5 linkuse as main transcriptc.2677T>G p.Ser893Ala missense_variant 22/29
ABCB1NM_001348944.2 linkuse as main transcriptc.2677T>G p.Ser893Ala missense_variant 23/30

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCB1ENST00000622132.5 linkuse as main transcriptc.2677T>G p.Ser893Ala missense_variant 21/281 NM_001348946.2 P1P08183-1

Frequencies

GnomAD3 genomes
AF:
0.641
AC:
97433
AN:
151960
Hom.:
33483
Cov.:
32
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.:
36
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.:
32
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/Likely benign
Submissions summary: Benign:3Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 27, 2014- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 13, 2018This 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. -
ABCB1-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 21, 2021This 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 providedliterature onlyOMIMDec 01, 2003- -
Tramadol response Other:1
drug response, no assertion criteria providedresearchBruce Budowle Laboratory, University of North Texas Health Science CenterApr 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
T
BayesDel_noAF
Benign
-0.46
Cadd
Benign
14
Dann
Benign
0.33
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.23
T;.;T
MetaRNN
Benign
0.0000010
T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
-1.0
N;N;.
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.36
T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.043
MPC
0.17
ClinPred
0.0027
T
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.

Other links and lift over

dbSNP: rs2032582; hg19: chr7-87160618; COSMIC: COSV55944840; API