rs72558200
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_000392.5(ABCC2):c.3449G>A(p.Arg1150His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 0 hom. )
Consequence
ABCC2
NM_000392.5 missense
NM_000392.5 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
?
Variant 10-99836125-G-A is Pathogenic according to our data. Variant chr10-99836125-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99836125-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC2 | NM_000392.5 | c.3449G>A | p.Arg1150His | missense_variant | 25/32 | ENST00000647814.1 | |
ABCC2 | XM_006717630.4 | c.2753G>A | p.Arg918His | missense_variant | 20/27 | ||
ABCC2 | XM_047424598.1 | c.3449G>A | p.Arg1150His | missense_variant | 25/26 | ||
ABCC2 | XR_945604.4 | n.3654G>A | non_coding_transcript_exon_variant | 25/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC2 | ENST00000647814.1 | c.3449G>A | p.Arg1150His | missense_variant | 25/32 | NM_000392.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251486Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135916
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GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55AN XY: 727190
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GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74324
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dubin-Johnson syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 22, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2001 | - - |
ABCC2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 30, 2023 | The ABCC2 c.3449G>A variant is predicted to result in the amino acid substitution p.Arg1150His. This variant has been reported in the compound heterozygous state in two sibling with Dubin-Johnson syndrome, and also in the homozygous state in 5 individuals from 4 families with Dubin-Johnson syndrome (Mor-Cohen et al. 2001. PubMed ID: 11477083). In vitro functional studies suggest that this variant impairs the transport activity of ABCC2 (Mor-Cohen et al. 2001. PubMed ID: 11477083). This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1150 of the ABCC2 protein (p.Arg1150His). This variant is present in population databases (rs72558200, gnomAD 0.01%). This missense change has been observed in individual(s) with Dubin-Johnson syndrome (PMID: 11477083). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8419). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ABCC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ABCC2 function (PMID: 11477083). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Polyphen
D;D
Vest4
0.81
MVP
0.98
MPC
0.30
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at