rs72558199
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000392.5(ABCC2):c.3196C>T(p.Arg1066*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,614,084 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00055 ( 1 hom. )
Consequence
ABCC2
NM_000392.5 stop_gained
NM_000392.5 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.67
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 10-99832069-C-T is Pathogenic according to our data. Variant chr10-99832069-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ABCC2 | NM_000392.5 | c.3196C>T | p.Arg1066* | stop_gained | 23/32 | ENST00000647814.1 | NP_000383.2 | |
| ABCC2 | XM_006717630.4 | c.2500C>T | p.Arg834* | stop_gained | 18/27 | XP_006717693.1 | ||
| ABCC2 | XM_047424598.1 | c.3196C>T | p.Arg1066* | stop_gained | 23/26 | XP_047280554.1 | ||
| ABCC2 | XR_945604.4 | n.3401C>T | non_coding_transcript_exon_variant | 23/30 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ABCC2 | ENST00000647814.1 | c.3196C>T | p.Arg1066* | stop_gained | 23/32 | NM_000392.5 | ENSP00000497274.1 |
Frequencies
GnomAD3 genomes 0.000506 AC: 77AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000422 AC: 106AN: 251482Hom.: 0 AF XY: 0.000397 AC XY: 54AN XY: 135914
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GnomAD4 exome AF: 0.000547 AC: 799AN: 1461872Hom.: 1 Cov.: 33 AF XY: 0.000547 AC XY: 398AN XY: 727240
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GnomAD4 genome 0.000506 AC: 77AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Arg1066*) in the ABCC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC2 are known to be pathogenic (PMID: 9185779, 16549534, 16952291). This variant is present in population databases (rs72558199, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Dubin-Johnson syndrome (PMID: 9185779, 10464142, 21044052). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31603). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 22, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Dubin-Johnson syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2024 | Variant summary: ABCC2 c.3196C>T (p.Arg1066X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00042 in 251482 control chromosomes (gnomAD). c.3196C>T has been reported in the literature in individuals affected with Dubin-Johnson Syndrome (e.g. Paulusma_1997). The following publication has been ascertained in the context of this evaluation (PMID: 9185779). ClinVar contains an entry for this variant (Variation ID: 31603). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The ABCC2 c.3196C>T (p.Arg1066Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg1066Ter variant has been reported in two studies in which it is found in a total of three individuals with Dubin-Johnson syndrome including in one in a homozygous state and in two siblings in a compound heterozygous state (Paulusma et al. 1997; Pacifico et al. 2010). The p.Arg1066Ter variant is reported with the allele frequency of 0.04% in gnomAD Exome and is novel (not in any individuals) in 1000 GenomesThis variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic with a status of criteria provided, multiple submitters, no conflicts. The nucleotide change in ABCC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The ABCC2 c.3196C>T (p.Arg1066Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg1066Ter variant has been reported in two studies in which it is found in a total of three individuals with Dubin-Johnson syndrome including in one in a homozygous state and in two siblings in a compound heterozygous state (Paulusma et al. 1997; Pacifico et al. 2010). Control data are unavailable for this variant, which is reported at a frequency 0.00139 in the European American population of the Exome Sequencing Project. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Arg1066Ter variant is classified as likely pathogenic for Dubin-Johnson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
ABCC2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2024 | The ABCC2 c.3196C>T variant is predicted to result in premature protein termination (p.Arg1066*). This variant has been reported to be causative for autosomal recessive Dubin-Johnson syndrome (Paulusma et al. 1997. PubMed ID: 9185779; Pacifico et al. 2010. PubMed ID: 21044052; Corpechot et al. 2020. PubMed ID: 31544333). This variant is reported in 0.06% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in ABCC2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
Vest4
0.83
GERP RS
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