rs7080681

Positions:

chr10-99800412-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000392.5(ABCC2):c.1058G>A(p.Arg353His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,614,130 control chromosomes in the GnomAD database, including 90 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 47 hom. )

Consequence

ABCC2
NM_000392.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.62

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=0.0019336939).

BP6

Variant 10-99800412-G-A is Benign according to our data. Variant chr10-99800412-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 298446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99800412-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2114/152268) while in subpopulation AFR AF= 0.0475 (1976/41560). AF 95% confidence interval is 0.0458. There are 43 homozygotes in gnomad4. There are 976 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC2	NM_000392.5 linkuse as main transcript	c.1058G>A	p.Arg353His	missense_variant	9/32	ENST00000647814.1	NP_000383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1 linkuse as main transcript	c.1058G>A	p.Arg353His	missense_variant	9/32		NM_000392.5	ENSP00000497274	P1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2103

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0474

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00393

AC:

988

AN:

251120

Hom.:

AF XY:

0.00279

AC XY:

378

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000476

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00163

AC:

2384

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1005

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0508

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000197

Gnomad4 OTH exome

AF:

0.00432

GnomAD4 genome

AF:

0.0139

AC:

2114

AN:

152268

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

976

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0475

Gnomad4 AMR

AF:

0.00588

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.0164

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0513

AC:

226

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00491

AC:

596

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

ABCC2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 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

0.067

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.068

DANN

Benign

0.92

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.28

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.58

.;N

REVEL

Benign

0.19

Sift

Benign

0.12

.;T

Sift4G

Benign

0.11

.;T

Polyphen

0.020

B;B

Vest4

0.10

MVP

0.59

MPC

0.043

ClinPred

0.0070

GERP RS

-12

Varity_R

0.022

gMVP

0.081

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