rs2229109

Variant names:

• chr7-87550493-C-T
• rs2229109
• NM_001348946.2:c.1199G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-87550493-C-T
• chr7-87550493-C-A

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.1199G>A​(p.Ser400Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,613,078 control chromosomes in the GnomAD database, including 1,007 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 0.026 (80 hom., cov: 33)
  • Exomes 𝑓: 0.033 (927 hom.)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0700
• Publications: 176 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=0.008169949).
• BP6: Variant 7-87550493-C-T is Benign according to our data. Variant chr7-87550493-C-T is described in ClinVar as Benign. ClinVar VariationId is 194008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0256 (3906/152282) while in subpopulation NFE AF = 0.0402 (2734/68006). AF 95% confidence interval is 0.0389. There are 80 homozygotes in GnomAd4. There are 1815 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3906 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.1199G>A	p.Ser400Asn	missense	Exon 11 of 28	NP_001335875.1	P08183-1
	ABCB1	NM_001348945.2		c.1409G>A	p.Ser470Asn	missense	Exon 15 of 32	NP_001335874.1
	ABCB1	NM_000927.5		c.1199G>A	p.Ser400Asn	missense	Exon 12 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.1199G>A	p.Ser400Asn	missense	Exon 11 of 28	ENSP00000478255.1	P08183-1
	ABCB1	ENST00000265724.8	TSL:1	c.1199G>A	p.Ser400Asn	missense	Exon 12 of 29	ENSP00000265724.3	P08183-1
	ABCB1	ENST00000890305.1		c.1199G>A	p.Ser400Asn	missense	Exon 10 of 27	ENSP00000560364.1

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3906 AN: 152164 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0274 AC: 6863 AN: 250840 AF XY: 0.0285

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0328 AC: 47905 AN: 1460796 Hom.: 927 Cov.: 33 AF XY: 0.0325 AC XY: 23654 AN XY: 726744

African (AFR) AF: 0.00502 AC: 168 AN: 33478

American (AMR) AF: 0.0182 AC: 815 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 707 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.0147 AC: 1271 AN: 86254

European-Finnish (FIN) AF: 0.0178 AC: 937 AN: 52634

Middle Eastern (MID) AF: 0.0321 AC: 185 AN: 5760

European-Non Finnish (NFE) AF: 0.0378 AC: 42070 AN: 1111756

Other (OTH) AF: 0.0290 AC: 1749 AN: 60378

GnomAD4 genome AF: 0.0256 AC: 3906 AN: 152282 Hom.: 80 Cov.: 33 AF XY: 0.0244 AC XY: 1815 AN XY: 74474

African (AFR) AF: 0.00715 AC: 297 AN: 41552

American (AMR) AF: 0.0279 AC: 426 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4834

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0402 AC: 2734 AN: 68006

Other (OTH) AF: 0.0350 AC: 74 AN: 2112

Alfa AF: 0.0347 Hom.: 413

Bravo AF: 0.0260

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0385 AC: 331

ExAC AF: 0.0290 AC: 3523

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0477

EpiControl AF: 0.0476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.070
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.26
Sift	Benign	0.36	T
Sift4G	Benign	0.33	T
Polyphen		0.0040	B
Vest4		0.024
MPC		0.20
ClinPred		0.0092	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.45
Mutation Taster		=91/9	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: rs2229109; hg19: chr7-87179809; COSMIC: COSV107220926; COSMIC: COSV107220926;