7-87531302-A-C

Variant names:

• chr7-87531302-A-C
• rs2032582
• NM_001348946.2:c.2677T>G
• ABCB1 p.Ser893Ala

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -13 classification points (ACMG Germline Pathogenicity v2019): 0P and 13B. BA1BP4BP6_Strong

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 cumulative frequency of 0.549 (AC=884,204) in the gnomAD database across 1,611,172 control chromosomes, including 250,710 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.917. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S893= (synonymous): Likely_benign (ClinVar VariationId 748845, 1 star); p.S893T: Benign (ClinVar VariationId 166619, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.64 (33550 hom., cov: 32)
  • Exomes 𝑓: 0.54 (217160 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:2
• Conservation: PhyloP100: 2.22
• Publications: 1596 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]

ABCB1 Gene-Disease associations (from GenCC):

• inflammatory bowel disease 13

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -13 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9174 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001348946.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.2677T>G	p.Ser893Ala	missense	Exon 21 of 28	NP_001335875.1	P08183-1
	ABCB1	NM_001348945.2		c.2887T>G	p.Ser963Ala	missense	Exon 25 of 32	NP_001335874.1
	ABCB1	NM_000927.5		c.2677T>G	p.Ser893Ala	missense	Exon 22 of 29	NP_000918.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.2677T>G	p.Ser893Ala	missense	Exon 21 of 28	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.2677T>G	p.Ser893Ala	missense	Exon 22 of 29	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000488737.6	TSL:1	n.319T>G		non_coding_transcript_exon	Exon 2 of 9

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

GnomAD2 exomes AF: 0.539 AC: 135082 AN: 250640 AF XY: 0.524

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 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

African (AFR) AF: 0.926 AC: 30932 AN: 33402

American (AMR) AF: 0.549 AC: 24522 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 16508 AN: 26092

East Asian (EAS) AF: 0.442 AC: 17501 AN: 39598

South Asian (SAS) AF: 0.350 AC: 30155 AN: 86212

European-Finnish (FIN) AF: 0.475 AC: 25288 AN: 53202

Middle Eastern (MID) AF: 0.560 AC: 3216 AN: 5744

European-Non Finnish (NFE) AF: 0.545 AC: 604939 AN: 1109954

Other (OTH) AF: 0.557 AC: 33572 AN: 60246

GnomAD4 genome AF: 0.642 AC: 97571 AN: 152078 Hom.: 33550 Cov.: 32 AF XY: 0.634 AC XY: 47095 AN XY: 74338

African (AFR) AF: 0.911 AC: 37810 AN: 41526

American (AMR) AF: 0.604 AC: 9216 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2180 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2449 AN: 5170

South Asian (SAS) AF: 0.358 AC: 1723 AN: 4818

European-Finnish (FIN) AF: 0.476 AC: 5029 AN: 10574

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37091 AN: 67942

Other (OTH) AF: 0.643 AC: 1359 AN: 2112

Alfa AF: 0.561 Hom.: 60461

Bravo AF: 0.679

EpiCase AF: 0.543

EpiControl AF: 0.545

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.430 AC: 52730 AN: 122658

Turkish Variome AF: 0.499 AC: 772 AN: 1546 Hom.: 190

ABraOM SABE-WGS-1171 AF: 0.653 AC: 1456 AN: 2230 Hom.: 490

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABCB1-related disorder (1)
-	-	1	Epilepsy (1)
-	-	1	not specified (1)
-	-	-	Inflammatory bowel disease 13 (1)
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.0	N
PhyloP100		2.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.54
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2032582;

hg19: chr7-87160618;

COSMIC: COSV55944840;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar