rs387907317
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_003742.4(ABCB11):c.3767_3768insC(p.Val1257GlyfsTer40) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T1256T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
ABCB11
NM_003742.4 frameshift, splice_region
NM_003742.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
ABCB11 (HGNC:42): (ATP binding cassette subfamily B member 11) The membrane-associated 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 MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-168923820-C-CG is Pathogenic according to our data. Variant chr2-168923820-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 6592.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB11 | NM_003742.4 | c.3767_3768insC | p.Val1257GlyfsTer40 | frameshift_variant, splice_region_variant | 28/28 | ENST00000650372.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB11 | ENST00000650372.1 | c.3767_3768insC | p.Val1257GlyfsTer40 | frameshift_variant, splice_region_variant | 28/28 | NM_003742.4 | P1 | ||
ABCB11 | ENST00000649448.1 | c.2144_2145insC | p.Val716GlyfsTer40 | frameshift_variant, splice_region_variant | 15/15 | ||||
ABCB11 | ENST00000648875.1 | c.226+836_226+837insC | intron_variant | ||||||
ABCB11 | ENST00000439188.1 | c.*2165_*2166insC | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 15/15 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 15, 2022 | This sequence change creates a premature translational stop signal (p.Val1257Glyfs*40) in the ABCB11 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the ABCB11 protein. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ABCB11 protein in which other variant(s) (p.Glu1302*) have been determined to be pathogenic (PMID: 18395098, 31015375). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 6592). This variant is also known as 3767‚àí3768 ins C. This premature translational stop signal has been observed in individual(s) with progressive familial intrahepatic cholestasis (PMID: 9806540). - |
Progressive familial intrahepatic cholestasis type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
Computational scores
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Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at