chr7-87544882-G-A

Variant names:

• chr7-87544882-G-A
• rs35023033
• NM_001348946.2:c.2005C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001348946.2(ABCB1):​c.2005C>T​(p.Arg669Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,614,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052506924).
• BS2: High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.2005C>T	p.Arg669Cys	missense_variant	Exon 16 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.2215C>T	p.Arg739Cys	missense_variant	Exon 20 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.2005C>T	p.Arg669Cys	missense_variant	Exon 17 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.2005C>T	p.Arg669Cys	missense_variant	Exon 18 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.2005C>T	p.Arg669Cys	missense_variant	Exon 16 of 28	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.2005C>T	p.Arg669Cys	missense_variant	Exon 17 of 29	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.1813C>T	p.Arg605Cys	missense_variant	Exon 16 of 28	5		ENSP00000444095.1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152126 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00838

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000613 AC: 154 AN: 251370 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135848

Gnomad AFR exome AF: 0.00830

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 366 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 160 AN XY: 727200

Gnomad4 AFR exome AF: 0.00824

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152244 Hom.: 1 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74440

Gnomad4 AFR AF: 0.00836

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.00269

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.75	T;.;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.9	.;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.024	.;D;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.016	B;B;.
Vest4		0.26
MVP		0.45
MPC		0.29
ClinPred		0.072	T
GERP RS		2.9
Varity_R		0.15
gMVP		0.42

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: rs35023033; hg19: chr7-87174198; COSMIC: COSV99713427; COSMIC: COSV99713427;