rs35023033

Positions:

• chr7-87544882-G-A
• chr7-87544882-G-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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R669H) has been classified as Uncertain significance.

• 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/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.2005C>T	p.Arg669Cys	missense_variant	16/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.2215C>T	p.Arg739Cys	missense_variant	20/32
ABCB1	NM_000927.5	c.2005C>T	p.Arg669Cys	missense_variant	17/29
ABCB1	NM_001348944.2	c.2005C>T	p.Arg669Cys	missense_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.2005C>T	p.Arg669Cys	missense_variant	16/28	1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.2005C>T	p.Arg669Cys	missense_variant	17/29	1		P1
ABCB1	ENST00000543898.5	c.1813C>T	p.Arg605Cys	missense_variant	16/28	5

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;.
MutationTaster	Benign	1.0	N;N
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;