chr7-87531302-A-C

Variant names:

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

Variant summary

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

The NM_001348945.2(ABCB1):​c.2887T>G​(p.Ser963Ala) 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. 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. S963Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.64 (33550 hom., cov: 32)
  • Exomes 𝑓: 0.54 (217160 hom.)
• Consequence: ABCB1 NM_001348945.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:2
• 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=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 Benign. ClinVar VariationId is 166622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348945.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	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
	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

Selected	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
	ABCB1	ENST00000265724.8	TSL:1	c.2677T>G	p.Ser893Ala	missense	Exon 22 of 29	ENSP00000265724.3
	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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABCB1-related disorder (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
Polyphen		0.0	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
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

Other links and lift over

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