rs2273697

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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:6

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
ABCC2	NM_000392.5 linkuse as main transcript	c.1249G>A	p.Val417Ile	missense_variant	10/32	ENST00000647814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1 linkuse as main transcript	c.1249G>A	p.Val417Ile	missense_variant	10/32		NM_000392.5	P1

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

GnomAD3 exomes

AF:

0.191

AC:

47979

AN:

251224

Hom.:

4877

AF XY:

0.197

AC XY:

26739

AN XY:

135788

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 SAS exome

AF:

0.278

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

Gnomad4 AMR exome

AF:

0.153

Gnomad4 ASJ exome

AF:

0.214

Gnomad4 EAS exome

AF:

0.108

Gnomad4 SAS exome

AF:

0.277

Gnomad4 FIN exome

AF:

0.166

Gnomad4 NFE exome

AF:

0.201

Gnomad4 OTH exome

AF:

0.188

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

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.206

Gnomad4 EAS

AF:

0.0958

Gnomad4 SAS

AF:

0.269

Gnomad4 FIN

AF:

0.159

Gnomad4 NFE

AF:

0.199

Gnomad4 OTH

AF:

0.193

Alfa

AF:

0.199

Hom.:

8081

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 25087612, 22318656, 21691255, 15821043) -

Dubin-Johnson syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 08, 2018

- -

ABCC2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2023

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

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.19

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

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