4-88131171-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004827.3(ABCG2):c.421C>A(p.Gln141Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,854 control chromosomes in the GnomAD database, including 12,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.093 ( 973 hom., cov: 32)

Exomes 𝑓: 0.11 ( 11106 hom. )

Consequence

ABCG2
NM_004827.3 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:1O:5

Conservation

PhyloP100: 1.82

Publications

1252 publications found

Variant links:

Genes affected

ABCG2 (HGNC:74): (ATP binding cassette subfamily G member 2 (JR blood group)) The membrane-associated protein encoded by this gene is included in 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 White subfamily. Alternatively referred to as a breast cancer resistance protein, this protein functions as a xenobiotic transporter which may play a major role in multi-drug resistance. It likely serves as a cellular defense mechanism in response to mitoxantrone and anthracycline exposure. Significant expression of this protein has been observed in the placenta, which may suggest a potential role for this molecule in placenta tissue. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ABCG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002105534).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004827.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCG2	NM_004827.3	MANE Select	c.421C>A	p.Gln141Lys	missense	Exon 5 of 16	NP_004818.2
ABCG2	NM_001348985.1		c.421C>A	p.Gln141Lys	missense	Exon 6 of 17	NP_001335914.1
ABCG2	NM_001348986.2		c.421C>A	p.Gln141Lys	missense	Exon 5 of 16	NP_001335915.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCG2	ENST00000237612.8	TSL:1 MANE Select	c.421C>A	p.Gln141Lys	missense	Exon 5 of 16	ENSP00000237612.3
ABCG2	ENST00000515655.5	TSL:1	c.421C>A	p.Gln141Lys	missense	Exon 5 of 16	ENSP00000426917.1
ABCG2	ENST00000889086.1		c.421C>A	p.Gln141Lys	missense	Exon 5 of 17	ENSP00000559145.1

Frequencies

GnomAD3 genomes

AF:

0.0929

AC:

14129

AN:

152046

Hom.:

968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0299

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0669

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.0952

Gnomad FIN

AF:

0.0703

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0880

GnomAD2 exomes

AF:

0.125

AC:

31308

AN:

251158

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.0265

Gnomad AMR exome

AF:

0.225

Gnomad ASJ exome

AF:

0.0653

Gnomad EAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.0724

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.114

AC:

166367

AN:

1461690

Hom.:

11106

Cov.:

AF XY:

0.112

AC XY:

81701

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.0230

AC:

771

AN:

33470

American (AMR)

AF:

0.215

AC:

9598

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0652

AC:

1704

AN:

26132

East Asian (EAS)

AF:

0.297

AC:

11774

AN:

39690

South Asian (SAS)

AF:

0.0899

AC:

7757

AN:

86256

European-Finnish (FIN)

AF:

0.0734

AC:

3921

AN:

53390

Middle Eastern (MID)

AF:

0.0570

AC:

329

AN:

5768

European-Non Finnish (NFE)

AF:

0.111

AC:

123466

AN:

1111878

Other (OTH)

AF:

0.117

AC:

7047

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

7803

15607

23410

31214

39017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4644

9288

13932

18576

23220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0930

AC:

14145

AN:

152164

Hom.:

973

Cov.:

AF XY:

0.0930

AC XY:

6922

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0298

AC:

1237

AN:

41540

American (AMR)

AF:

0.138

AC:

2110

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0669

AC:

232

AN:

3468

East Asian (EAS)

AF:

0.310

AC:

1599

AN:

5158

South Asian (SAS)

AF:

0.0946

AC:

455

AN:

4808

European-Finnish (FIN)

AF:

0.0703

AC:

745

AN:

10600

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7428

AN:

67994

Other (OTH)

AF:

0.0890

AC:

188

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

643

1286

1928

2571

3214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.100

Hom.:

2431

Bravo

AF:

0.0987

TwinsUK

AF:

0.112

AC:

414

ALSPAC

AF:

0.104

AC:

400

ESP6500AA

AF:

0.0322

AC:

142

ESP6500EA

AF:

0.111

AC:

957

ExAC

AF:

0.118

AC:

14325

Asia WGS

AF:

0.174

AC:

603

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

ABCG2-related disorder (1)

BLOOD GROUP, JUNIOR SYSTEM (1)

Gemcitabine response (1)

rosuvastatin response - Efficacy (1)

rosuvastatin response - Metabolism/PK (1)

URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Benign

-0.025

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.33

PhyloP100

1.8

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.14

Sift4G

Benign

0.71

Polyphen

0.44

Vest4

0.17

MPC

0.037

ClinPred

0.033

GERP RS

5.4

Varity_R

0.70

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over