rs917981474
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_003742.4(ABCB11):c.1763C>T(p.Ala588Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,804 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A588G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003742.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB11 | NM_003742.4 | c.1763C>T | p.Ala588Val | missense_variant | 15/28 | ENST00000650372.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB11 | ENST00000650372.1 | c.1763C>T | p.Ala588Val | missense_variant | 15/28 | NM_003742.4 | P1 | ||
ABCB11 | ENST00000649448.1 | c.80C>T | p.Ala27Val | missense_variant | 1/15 | ||||
ABCB11 | ENST00000478354.1 | n.501C>T | non_coding_transcript_exon_variant | 1/2 | 4 | ||||
ABCB11 | ENST00000439188.1 | c.*233C>T | 3_prime_UTR_variant, NMD_transcript_variant | 2/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151944Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248624Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134876
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1460860Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726736
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151944Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74186
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 19101985). 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. ClinVar contains an entry for this variant (Variation ID: 594531). This variant is also known as p.Ala558Val. This missense change has been observed in individuals with ABCB11-related conditions (PMID: 18395098, 34016879). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 588 of the ABCB11 protein (p.Ala588Val). - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 31, 2018 | - - |
Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 06, 2023 | - - |
Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 09, 2022 | - - |
Progressive familial intrahepatic cholestasis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 02, 2021 | Variant summary: ABCB11 c.1763C>T (p.Ala588Val) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) 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 8e-06 in 248624 control chromosomes (gomAD). c.1763C>T has been reported in the literature in homozygous and compound heterozygous state in multiple individuals affected with Familial Intrahepatic Cholestasis (Walkowiak_2006, Strautnieks_2008, Zhang_2020, Hertel_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that although the variant didn't cause aberrant splicing in a minigene assay, however it resulted in the absence of protein product, indicating that the variant protein was rapidly degraded (Byrne_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as 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