rs2032582

chr7-87531302-A-Cchr7-87531302-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

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 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: 2.22

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 -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
ABCB1	NM_001348946.2	c.2677T>G	p.Ser893Ala	missense_variant	21/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.2887T>G	p.Ser963Ala	missense_variant	25/32
ABCB1	NM_000927.5	c.2677T>G	p.Ser893Ala	missense_variant	22/29
ABCB1	NM_001348944.2	c.2677T>G	p.Ser893Ala	missense_variant	23/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.2677T>G	p.Ser893Ala	missense_variant	21/28	1	NM_001348946.2	P1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97433 AN: 151960 Hom.: 33483 Cov.: 32

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

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

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

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:3 Other:2

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)

Jan 27, 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. -

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	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

Other links and lift over

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