NM_000392.5:c.3542G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000392.5(ABCC2):c.3542G>A(p.Arg1181Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00041 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1181L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

ABCC2
NM_000392.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.87

Publications

29 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5 link	c.3542G>A	p.Arg1181Gln	missense_variant	Exon 25 of 32	ENST00000647814.1	NP_000383.2	Q92887
ABCC2	XM_006717630.4 link	c.2846G>A	p.Arg949Gln	missense_variant	Exon 20 of 27		XP_006717693.1
ABCC2	XM_047424598.1 link	c.3542G>A	p.Arg1181Gln	missense_variant	Exon 25 of 26		XP_047280554.1
ABCC2	XR_945604.4 link	n.3747G>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.3542G>A	p.Arg1181Gln	missense_variant	Exon 25 of 32	NM_000392.5	ENSP00000497274.1	Q92887
ENSG00000295976	ENST00000734671.1 link	n.51-2039C>T		intron_variant	Intron 1 of 1
ENSG00000295976	ENST00000734672.1 link	n.523-2039C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000378

AC:

AN:

251486

AF XY:

0.000375

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000430

AC:

629

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

301

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000518

AC:

576

AN:

1112004

Other (OTH)

AF:

0.000265

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000210

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00319

Hom.:

114

Bravo

AF:

0.000268

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dubin-Johnson syndrome

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D

M_CAP

Uncertain

0.099

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.9

M;M

PhyloP100

6.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

.;N

REVEL

Pathogenic

0.77

Sift

Uncertain

0.019

.;D

Sift4G

Uncertain

0.036

.;D

Polyphen

1.0

D;D

Vest4

0.50

MutPred

0.48

Gain of ubiquitination at K1184 (P = 0.0546);Gain of ubiquitination at K1184 (P = 0.0546);

MVP

0.94

MPC

0.29

ClinPred

0.29

GERP RS

3.9

Varity_R

0.60

gMVP

0.50

Mutation Taster

=88/12

polymorphism

(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