rs386834115
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_017890.5(VPS13B):c.8697-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_017890.5 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.8697-2A>G | splice_acceptor_variant | ENST00000358544.7 | |||
VPS13B | NM_152564.5 | c.8622-2A>G | splice_acceptor_variant | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.8622-2A>G | splice_acceptor_variant | 1 | NM_152564.5 | P1 | |||
VPS13B | ENST00000358544.7 | c.8697-2A>G | splice_acceptor_variant | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461280Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726956
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 19, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with Cohen syndrome (PMID: 15141358). ClinVar contains an entry for this variant (Variation ID: 56696). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 47 of the VPS13B 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 VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at