10-99836193-A-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000392.5(ABCC2):c.3517A>T(p.Ile1173Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,090 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
ABCC2
NM_000392.5 missense
NM_000392.5 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.29
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 12 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 10-99836193-A-T is Pathogenic according to our data. Variant chr10-99836193-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8418.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.3517A>T | p.Ile1173Phe | missense_variant | 25/32 | ENST00000647814.1 | NP_000383.2 | |
ABCC2 | XM_006717630.4 | c.2821A>T | p.Ile941Phe | missense_variant | 20/27 | XP_006717693.1 | ||
ABCC2 | XM_047424598.1 | c.3517A>T | p.Ile1173Phe | missense_variant | 25/26 | XP_047280554.1 | ||
ABCC2 | XR_945604.4 | n.3722A>T | non_coding_transcript_exon_variant | 25/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC2 | ENST00000647814.1 | c.3517A>T | p.Ile1173Phe | missense_variant | 25/32 | NM_000392.5 | ENSP00000497274.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251492Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135922
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727248
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dubin-Johnson syndrome Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | FirmaLab, FirmaLab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 06, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The ABCC2 c.3517A>T (p.Ile1173Phe) missense variant has been reported in a single study in which it was found in a total of 24 individuals with Dubin-Johnson syndrome, including in a homozygous state in 22 patients of Iranian Jewish origin and in a compound heterozygous state in two patients of mixed Iranian Jewish and Moroccan Jewish origin (Mor-Cohen et al. 2001). The p.Ile1173Phe variant was also detected in a heterozygous state in 14 of 243 healthy Iranian Jewish controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Expression studies indicated that the p.Ile1173Phe variant resulted in impaired transport activity of the ABCC2 protein, expression of the variant protein was low, and the variant protein itself mislocated to the endoplasmic reticulum (Mor-Cohen et al. 2001). Based on the collective evidence, the p.Ile1173Phe variant is classified as pathogenic for Dubin-Johnson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 17, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 27, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the ABCC2 protein (p.Ile1173Phe). This variant is present in population databases (rs72558201, gnomAD 0.004%). This missense change has been observed in individuals with Dubin-Johnson syndrome (PMID: 11477083, 31544333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8418). 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 expected to disrupt ABCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ABCC2 function (PMID: 11477083, 12388192, 22290738). 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
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D
REVEL
Pathogenic
Sift
Pathogenic
.;D
Sift4G
Pathogenic
.;D
Polyphen
D;D
Vest4
0.93
MutPred
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
0.87
MPC
0.32
ClinPred
D
GERP RS
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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