rs763782349
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003742.4(ABCB11):c.2296G>A(p.Gly766Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,304 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G766G) has been classified as Likely benign.
Frequency
Consequence
NM_003742.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB11 | NM_003742.4 | c.2296G>A | p.Gly766Arg | missense_variant | 19/28 | ENST00000650372.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB11 | ENST00000650372.1 | c.2296G>A | p.Gly766Arg | missense_variant | 19/28 | NM_003742.4 | P1 | ||
ABCB11 | ENST00000649448.1 | c.613G>A | p.Gly205Arg | missense_variant | 5/15 | ||||
ABCB11 | ENST00000439188.1 | c.*766G>A | 3_prime_UTR_variant, NMD_transcript_variant | 6/15 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000283 AC: 7AN: 247288Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134188
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1457304Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 724674
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Progressive familial intrahepatic cholestasis type 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rolfs Rare Disease Consulting, Rolfs Consulting Und Verwaltungs GmbH | Jan 01, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 02, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 766 of the ABCB11 protein (p.Gly766Arg). This variant is present in population databases (rs763782349, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of progressive familial intrahepatic cholestasis (PMID: 18395098, 21490445, 28733223). This gene is also known as BSEP. ClinVar contains an entry for this variant (Variation ID: 290133). 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 ABCB11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 14, 2017 | - - |
ABCB11-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 08, 2024 | The ABCB11 c.2296G>A variant is predicted to result in the amino acid substitution p.Gly766Arg. This variant has been reported in the homozygous, heterozygous, and compound heterozygous state in multiple unrelated patients affected with progressive familial intrahepatic cholestasis (Strautnieks et al. 2008. PubMed ID: 18395098; Evason et al. 2011. PubMed ID: 21490445; Park et al. 2016. PubMed ID: 27239116; Dröge et al. 2017. PubMed ID: 28733223). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Based on the available evidence, we classify this variant as pathogenic. - |
Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
Progressive familial intrahepatic cholestasis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 30, 2023 | Variant summary: ABCB11 c.2296G>A (p.Gly766Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 247288 control chromosomes (gnomAD). c.2296G>A has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (Strautnieks_2008, Evason_2011, Droge_2017, Hertel_2021), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18395098, 21490445, 28733223, 34016879). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at