7-87561309-T-C

Variant names:

• chr7-87561309-T-C
• rs36008564
• NM_001348946.2:c.781A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.898
• Publications: 13 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 -20 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 VariationId is 711479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 892 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348946.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	NM_001348946.2	MANE Select	c.781A>G	p.Ile261Val	missense	Exon 8 of 28	NP_001335875.1	P08183-1
	ABCB1	NM_001348945.2		c.991A>G	p.Ile331Val	missense	Exon 12 of 32	NP_001335874.1
	ABCB1	NM_000927.5		c.781A>G	p.Ile261Val	missense	Exon 9 of 29	NP_000918.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB1	ENST00000622132.5	TSL:1 MANE Select	c.781A>G	p.Ile261Val	missense	Exon 8 of 28	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.781A>G	p.Ile261Val	missense	Exon 9 of 29	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000890305.1		c.781A>G	p.Ile261Val	missense	Exon 7 of 27	ENSP00000560364.1

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

GnomAD2 exomes AF: 0.00247 AC: 620 AN: 251310 AF XY: 0.00219

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 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

African (AFR) AF: 0.0169 AC: 565 AN: 33476

American (AMR) AF: 0.00396 AC: 177 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00735 AC: 192 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5766

European-Non Finnish (NFE) AF: 0.000670 AC: 745 AN: 1111954

Other (OTH) AF: 0.00356 AC: 215 AN: 60378

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

African (AFR) AF: 0.0164 AC: 682 AN: 41586

American (AMR) AF: 0.00549 AC: 84 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68024

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00299 Hom.: 7

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.90
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.26
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Polyphen		0.052	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
Mutation Taster		=95/5	polymorphism

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