10-99836218-G-T

Position:

chr10-99836218-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000392.5(ABCC2):c.3542G>T(p.Arg1181Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00531 in 1,614,136 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1181Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 197 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 164 hom. )

Consequence

ABCC2
NM_000392.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.87

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=0.0073453486).

BP6

Variant 10-99836218-G-T is Benign according to our data. Variant chr10-99836218-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 195851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99836218-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC2	NM_000392.5 linkuse as main transcript	c.3542G>T	p.Arg1181Leu	missense_variant	25/32	ENST00000647814.1
ABCC2	XM_006717630.4 linkuse as main transcript	c.2846G>T	p.Arg949Leu	missense_variant	20/27
ABCC2	XM_047424598.1 linkuse as main transcript	c.3542G>T	p.Arg1181Leu	missense_variant	25/26
ABCC2	XR_945604.4 linkuse as main transcript	n.3747G>T		non_coding_transcript_exon_variant	25/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1 linkuse as main transcript	c.3542G>T	p.Arg1181Leu	missense_variant	25/32		NM_000392.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4113

AN:

152142

Hom.:

198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0923

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.00754

AC:

1895

AN:

251486

Hom.:

AF XY:

0.00549

AC XY:

746

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0971

Gnomad AMR exome

AF:

0.00636

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000492

Gnomad OTH exome

AF:

0.00521

GnomAD4 exome

AF:

0.00305

AC:

4459

AN:

1461876

Hom.:

164

Cov.:

AF XY:

0.00264

AC XY:

1917

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0949

Gnomad4 AMR exome

AF:

0.00695

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000429

Gnomad4 OTH exome

AF:

0.00687

GnomAD4 genome

AF:

0.0271

AC:

4120

AN:

152260

Hom.:

197

Cov.:

AF XY:

0.0260

AC XY:

1938

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0922

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.0314

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0944

AC:

416

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00923

AC:

1121

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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	Jun 09, 2021	This variant is associated with the following publications: (PMID: 22290738) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 02, 2015

- -

ABCC2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.5

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

Polyphen

1.0

D;D

Vest4

0.89

MVP

0.86

MPC

0.29

ClinPred

0.062

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.70

gMVP

0.64

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

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