7-87600124-T-C

Variant names:

• chr7-87600124-T-C
• rs9282564
• NM_001348946.2:c.61A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001348946.2(ABCB1):​c.61A>G​(p.Asn21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,612,594 control chromosomes in the GnomAD database, including 8,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.071 (633 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7733 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Likely benign; drug response no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: -0.196

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015675128).
• BP6: Variant 7-87600124-T-C is Benign according to our data. Variant chr7-87600124-T-C is described in ClinVar as [Likely_benign, drug_response]. Clinvar id is 829327.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.61A>G	p.Asn21Asp	missense_variant	Exon 2 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.271A>G	p.Asn91Asp	missense_variant	Exon 6 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.61A>G	p.Asn21Asp	missense_variant	Exon 3 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.61A>G	p.Asn21Asp	missense_variant	Exon 4 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.61A>G	p.Asn21Asp	missense_variant	Exon 2 of 28	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.61A>G	p.Asn21Asp	missense_variant	Exon 3 of 29	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.61A>G	p.Asn21Asp	missense_variant	Exon 3 of 28	5		ENSP00000444095.1
ABCB1	ENST00000416177.1	c.61A>G	p.Asn21Asp	missense_variant	Exon 4 of 6	5		ENSP00000399419.1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10852 AN: 152176 Hom.: 633 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0398

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0731 AC: 18331 AN: 250642 AF XY: 0.0741

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0940 AC: 137226 AN: 1460300 Hom.: 7733 Cov.: 30 AF XY: 0.0922 AC XY: 66983 AN XY: 726490

Gnomad4 AFR exome AF: 0.0133 AC: 445 AN: 33462

Gnomad4 AMR exome AF: 0.0302 AC: 1348 AN: 44700

Gnomad4 ASJ exome AF: 0.0232 AC: 605 AN: 26130

Gnomad4 EAS exome AF: 0.000151 AC: 6 AN: 39692

Gnomad4 SAS exome AF: 0.0257 AC: 2217 AN: 86180

Gnomad4 FIN exome AF: 0.169 AC: 9024 AN: 53372

Gnomad4 NFE exome AF: 0.107 AC: 118956 AN: 1110670

Gnomad4 Remaining exome AF: 0.0757 AC: 4567 AN: 60330

GnomAD4 genome AF: 0.0712 AC: 10849 AN: 152294 Hom.: 633 Cov.: 32 AF XY: 0.0718 AC XY: 5346 AN XY: 74472

Gnomad4 AFR AF: 0.0158 AC: 0.0158054 AN: 0.0158054

Gnomad4 AMR AF: 0.0397 AC: 0.0397334 AN: 0.0397334

Gnomad4 ASJ AF: 0.0179 AC: 0.0178571 AN: 0.0178571

Gnomad4 EAS AF: 0.000193 AC: 0.000192604 AN: 0.000192604

Gnomad4 SAS AF: 0.0251 AC: 0.0250621 AN: 0.0250621

Gnomad4 FIN AF: 0.176 AC: 0.175722 AN: 0.175722

Gnomad4 NFE AF: 0.108 AC: 0.108051 AN: 0.108051

Gnomad4 OTH AF: 0.0473 AC: 0.0473485 AN: 0.0473485

Alfa AF: 0.0867 Hom.: 3257

Bravo AF: 0.0579

TwinsUK AF: 0.103 AC: 382

ALSPAC AF: 0.0991 AC: 382

ESP6500AA AF: 0.0270 AC: 119

ESP6500EA AF: 0.0997 AC: 857

ExAC AF: 0.0758 AC: 9204

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Likely benign; drug response

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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). -

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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	0.059
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.2
DANN	Benign	0.36
DEOGEN2	Benign	0.052	.;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.50	T;.;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.49	.;N;N;D
REVEL	Benign	0.17
Sift	Benign	0.50	.;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0020	B;B;.;.
Vest4		0.039
MPC		0.24
ClinPred		0.000071	T
GERP RS		-2.7
Varity_R		0.042
gMVP		0.068
Mutation Taster		=97/3	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

Publications

LitVar

Other links and lift over

dbSNP: rs9282564; hg19: chr7-87229440; COSMIC: COSV55944435; COSMIC: COSV55944435;