rs2273697

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.1249G>A(p.Val417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,613,940 control chromosomes in the GnomAD database, including 32,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V417A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 2730 hom., cov: 32)

Exomes 𝑓: 0.20 ( 29948 hom. )

Consequence

ABCC2
NM_000392.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.327

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 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=0.00972563).

BP6

Variant 10-99804058-G-A is Benign according to our data. Variant chr10-99804058-G-A is described in ClinVar as [Benign]. Clinvar id is 255992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99804058-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5 link	c.1249G>A	p.Val417Ile	missense_variant	Exon 10 of 32	ENST00000647814.1	NP_000383.2	Q92887

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1 link	c.1249G>A	p.Val417Ile	missense_variant	Exon 10 of 32		NM_000392.5	ENSP00000497274.1		Q92887

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28258

AN:

152000

Hom.:

2734

Cov.:

show subpopulations

Gnomad AFR

AF:

0.182

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.0958

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.191

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.191

AC:

47979

AN:

251224

AF XY:

0.197

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.0875

Gnomad FIN exome

AF:

0.164

Gnomad NFE exome

AF:

0.199

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.200

AC:

292615

AN:

1461822

Hom.:

29948

Cov.:

AF XY:

0.203

AC XY:

147754

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.187

AC:

6262

AN:

33476

Gnomad4 AMR exome

AF:

0.153

AC:

6841

AN:

44718

Gnomad4 ASJ exome

AF:

0.214

AC:

5600

AN:

26136

Gnomad4 EAS exome

AF:

0.108

AC:

4279

AN:

39696

Gnomad4 SAS exome

AF:

0.277

AC:

23890

AN:

86256

Gnomad4 FIN exome

AF:

0.166

AC:

8884

AN:

53418

Gnomad4 NFE exome

AF:

0.201

AC:

223982

AN:

1111962

Gnomad4 Remaining exome

AF:

0.188

AC:

11348

AN:

60392

Heterozygous variant carriers

14184

28369

42553

56738

70922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

7808

15616

23424

31232

39040

<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:

0.186

AC:

28256

AN:

152118

Hom.:

2730

Cov.:

AF XY:

0.182

AC XY:

13569

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.182

AC:

0.181985

AN:

0.181985

Gnomad4 AMR

AF:

0.158

AC:

0.157781

AN:

0.157781

Gnomad4 ASJ

AF:

0.206

AC:

0.205594

AN:

0.205594

Gnomad4 EAS

AF:

0.0958

AC:

0.0958269

AN:

0.0958269

Gnomad4 SAS

AF:

0.269

AC:

0.268592

AN:

0.268592

Gnomad4 FIN

AF:

0.159

AC:

0.15855

AN:

0.15855

Gnomad4 NFE

AF:

0.199

AC:

0.199165

AN:

0.199165

Gnomad4 OTH

AF:

0.193

AC:

0.192526

AN:

0.192526

Heterozygous variant carriers

1171

2342

3514

4685

5856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.196

Hom.:

11368

Bravo

AF:

0.186

TwinsUK

AF:

0.210

AC:

779

ALSPAC

AF:

0.203

AC:

781

ESP6500AA

AF:

0.187

AC:

824

ESP6500EA

AF:

0.195

AC:

1675

ExAC

AF:

0.195

AC:

23702

Asia WGS

AF:

0.161

AC:

562

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.211

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, 22318656, 21691255, 15821043) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dubin-Johnson syndrome

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:1

May 08, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCC2-related disorder

Benign:1

Jan 16, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.023

DANN

Benign

0.76

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.71

.;T

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.63

.;N

REVEL

Benign

0.23

Sift

Benign

0.16

.;T

Sift4G

Benign

0.16

.;T

Polyphen

0.0080

B;B

Vest4

0.018

MPC

0.036

ClinPred

0.010

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.22

Mutation Taster

=95/5

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over