rs36008564

chr7-87561309-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001348946.2(ABCB1):c.781A>G(p.Ile261Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,096 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0059 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.898

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011926174).
• BP6: Variant 7-87561309-T-C is Benign according to our data. Variant chr7-87561309-T-C is described in ClinVar as [Benign]. Clinvar id is 711479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00585 (892/152352) while in subpopulation AFR AF= 0.0164 (682/41586). AF 95% confidence interval is 0.0154. There are 14 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 894 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB1	NM_001348946.2	c.781A>G	p.Ile261Val	missense_variant	8/28	ENST00000622132.5
ABCB1	NM_001348945.2	c.991A>G	p.Ile331Val	missense_variant	12/32
ABCB1	NM_000927.5	c.781A>G	p.Ile261Val	missense_variant	9/29
ABCB1	NM_001348944.2	c.781A>G	p.Ile261Val	missense_variant	10/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB1	ENST00000622132.5	c.781A>G	p.Ile261Val	missense_variant	8/28	1	NM_001348946.2	P1
ABCB1	ENST00000265724.8	c.781A>G	p.Ile261Val	missense_variant	9/29	1		P1
ABCB1	ENST00000543898.5	c.589A>G	p.Ile197Val	missense_variant	8/28	5

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 894 AN: 152234 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00247 AC: 620 AN: 251310 Hom.: 4 AF XY: 0.00219 AC XY: 297 AN XY: 135836

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00134 AC: 1964 AN: 1461744 Hom.: 7 Cov.: 31 AF XY: 0.00130 AC XY: 945 AN XY: 727168

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000670

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.00585 AC: 892 AN: 152352 Hom.: 14 Cov.: 33 AF XY: 0.00588 AC XY: 438 AN XY: 74510

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00203 Hom.: 3

Bravo AF: 0.00713

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00244 AC: 296

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.0065
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.89	D;.;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.052	B;B;.
Vest4		0.11
MVP		0.49
MPC		0.19
ClinPred		0.017	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.74

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: rs36008564; hg19: chr7-87190625; COSMIC: COSV55949049;