chr7-87531302-A-T

Variant names:

• chr7-87531302-A-T
• rs2032582
• NM_001348946.2:c.2677T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_001348946.2(ABCB1):​c.2677T>A​(p.Ser893Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,612,540 control chromosomes in the GnomAD database, including 1,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 0.024 (98 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1006 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.22
• Publications: 1557 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 1164001.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018371046).
• BP6: Variant 7-87531302-A-T is Benign according to our data. Variant chr7-87531302-A-T is described in ClinVar as Benign. ClinVar VariationId is 166619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.2677T>A	p.Ser893Thr	missense_variant	Exon 21 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.2887T>A	p.Ser963Thr	missense_variant	Exon 25 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.2677T>A	p.Ser893Thr	missense_variant	Exon 22 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.2677T>A	p.Ser893Thr	missense_variant	Exon 23 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.2677T>A	p.Ser893Thr	missense_variant	Exon 21 of 28	1	NM_001348946.2	ENSP00000478255.1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3636 AN: 152006 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0500

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0377 AC: 9446 AN: 250640 AF XY: 0.0366

Gnomad AFR exome AF: 0.00419

Gnomad AMR exome AF: 0.0540

Gnomad ASJ exome AF: 0.0263

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.0351

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0266 AC: 38819 AN: 1460416 Hom.: 1006 Cov.: 36 AF XY: 0.0270 AC XY: 19614 AN XY: 726546

African (AFR) AF: 0.00305 AC: 102 AN: 33402

American (AMR) AF: 0.0522 AC: 2330 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0250 AC: 654 AN: 26110

East Asian (EAS) AF: 0.156 AC: 6190 AN: 39598

South Asian (SAS) AF: 0.0444 AC: 3825 AN: 86232

European-Finnish (FIN) AF: 0.0357 AC: 1902 AN: 53226

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5750

European-Non Finnish (NFE) AF: 0.0199 AC: 22076 AN: 1111142

Other (OTH) AF: 0.0268 AC: 1619 AN: 60308

GnomAD4 genome AF: 0.0239 AC: 3634 AN: 152124 Hom.: 98 Cov.: 32 AF XY: 0.0254 AC XY: 1888 AN XY: 74356

African (AFR) AF: 0.00443 AC: 184 AN: 41540

American (AMR) AF: 0.0342 AC: 522 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3470

East Asian (EAS) AF: 0.135 AC: 696 AN: 5170

South Asian (SAS) AF: 0.0492 AC: 237 AN: 4820

European-Finnish (FIN) AF: 0.0313 AC: 331 AN: 10576

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1451 AN: 67958

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.000896 Hom.: 60461

TwinsUK AF: 0.0205 AC: 76

ExAC AF: 0.0371 AC: 4507

EpiCase AF: 0.0207

EpiControl AF: 0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCB1-related disorder Benign:1

Jul 21, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.0	.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
LIST_S2	Benign	0.55	T;.;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	M;M;.
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.0	.;N;N
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.024	D;D;D
Vest4		0.088
ClinPred		0.018	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.74
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2032582; hg19: chr7-87160618; COSMIC: COSV108734133;