rs34937870
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_000392.5(ABCC2):c.3741+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000392.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC2 | NM_000392.5 | c.3741+1G>A | splice_donor_variant | ENST00000647814.1 | |||
ABCC2 | XM_006717630.4 | c.3045+1G>A | splice_donor_variant | ||||
ABCC2 | XM_047424598.1 | c.3615-1705G>A | intron_variant | ||||
ABCC2 | XR_945604.4 | n.3946+1G>A | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC2 | ENST00000647814.1 | c.3741+1G>A | splice_donor_variant | NM_000392.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251470Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135912
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727222
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74486
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 27, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change affects a donor splice site in intron 26 of the ABCC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCC2 are known to be pathogenic (PMID: 9185779, 16549534, 16952291). This variant is present in population databases (rs34937870, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of Dubin-Johnson syndrome (PMID: 31544333). ClinVar contains an entry for this variant (Variation ID: 208557). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Dubin-Johnson syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 22, 2014 | The c.3741+1G>A variant in ABCC2 has not been previously reported in individuals with disease. It has been identified in 1/11606 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs34937870). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Homozygous or compound heterozygous loss of function in the ABCC2 gene has been shown to cause Dubin-Johnson syndrome. In summary, this variant meets our criteria to be classified as pathogenic for Dubin-Johnson syndrome in an autosomal recessive manner. - |
ABCC2-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2024 | The ABCC2 c.3741+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. A different variant impacting the same nucelotide position (c.3741+1G>T) has been reported in the compound heterozygous state in an individual presenting with Dubin-Johnson syndrome (Table 1, Corpechot et al. 2019. PubMed ID: 31544333). Variants that disrupt the consensus splice donor site in ABCC2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at