rs17222723

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000392.5(ABCC2):c.3563T>A(p.Val1188Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,613,986 control chromosomes in the GnomAD database, including 2,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.054 ( 249 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2347 hom. )

Consequence

ABCC2
NM_000392.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.72

Publications

101 publications found

Variant links:

Genes affected

ABCC2 (HGNC:53): (ATP binding cassette subfamily C member 2) The 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 MRP subfamily which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells. Several different mutations in this gene have been observed in patients with Dubin-Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia. [provided by RefSeq, Jul 2008]

ABCC2 Gene-Disease associations (from GenCC):

Dubin-Johnson syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ABCC2 links:

ENSG00000295976 (HGNC:):

ENSG00000295976 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002881676).

BP6

Variant 10-99836239-T-A is Benign according to our data. Variant chr10-99836239-T-A is described in ClinVar as Benign. ClinVar VariationId is 298467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5 link	c.3563T>A	p.Val1188Glu	missense_variant	Exon 25 of 32	ENST00000647814.1	NP_000383.2	Q92887
ABCC2	XM_006717630.4 link	c.2867T>A	p.Val956Glu	missense_variant	Exon 20 of 27		XP_006717693.1
ABCC2	XM_047424598.1 link	c.3563T>A	p.Val1188Glu	missense_variant	Exon 25 of 26		XP_047280554.1
ABCC2	XR_945604.4 link	n.3768T>A		non_coding_transcript_exon_variant	Exon 25 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	ENST00000647814.1 link	c.3563T>A	p.Val1188Glu	missense_variant	Exon 25 of 32	NM_000392.5	ENSP00000497274.1	Q92887
ENSG00000295976	ENST00000734671.1 link	n.51-2060A>T		intron_variant	Intron 1 of 1
ENSG00000295976	ENST00000734672.1 link	n.523-2060A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0539

AC:

8202

AN:

152062

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0594

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0579

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0709

GnomAD2 exomes

AF:

0.0453

AC:

11386

AN:

251494

AF XY:

0.0457

show subpopulations

Gnomad AFR exome

AF:

0.0585

Gnomad AMR exome

AF:

0.0360

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.0225

Gnomad NFE exome

AF:

0.0568

Gnomad OTH exome

AF:

0.0611

GnomAD4 exome

AF:

0.0531

AC:

77680

AN:

1461806

Hom.:

2347

Cov.:

AF XY:

0.0525

AC XY:

38200

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0607

AC:

2032

AN:

33478

American (AMR)

AF:

0.0390

AC:

1746

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

3426

AN:

26136

East Asian (EAS)

AF:

0.000327

AC:

AN:

39700

South Asian (SAS)

AF:

0.0186

AC:

1603

AN:

86248

European-Finnish (FIN)

AF:

0.0232

AC:

1238

AN:

53416

Middle Eastern (MID)

AF:

0.129

AC:

744

AN:

5766

European-Non Finnish (NFE)

AF:

0.0569

AC:

63242

AN:

1111948

Other (OTH)

AF:

0.0602

AC:

3636

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4536

9072

13607

18143

22679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2372

4744

7116

9488

11860

<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:

0.0540

AC:

8223

AN:

152180

Hom.:

249

Cov.:

AF XY:

0.0523

AC XY:

3891

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0599

AC:

2487

AN:

41508

American (AMR)

AF:

0.0579

AC:

885

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

423

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.0205

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0225

AC:

238

AN:

10600

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0567

AC:

3858

AN:

67996

Other (OTH)

AF:

0.0707

AC:

149

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

387

774

1160

1547

1934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0604

Hom.:

260

Bravo

AF:

0.0586

TwinsUK

AF:

0.0607

AC:

225

ALSPAC

AF:

0.0555

AC:

214

ESP6500AA

AF:

0.0595

AC:

262

ESP6500EA

AF:

0.0617

AC:

531

ExAC

AF:

0.0430

AC:

5221

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0661

EpiControl

AF:

0.0727

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25087612, 18926681, 16628674) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCC2-related disorder

Benign:1

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dubin-Johnson syndrome

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.0030

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.088

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.19

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.52

N;N

PhyloP100

-2.7

PrimateAI

Benign

0.26

PROVEAN

Benign

0.71

.;N

REVEL

Benign

0.21

Sift

Benign

0.97

.;T

Sift4G

Benign

1.0

.;T

Polyphen

0.0

B;B

Vest4

0.097

MPC

0.051

ClinPred

0.0029

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.089

gMVP

0.28

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over