rs1553268799
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePM2PP3PP5_Moderate
The NM_000447.3(PSEN2):c.886+2_886+4del variant causes a splice donor, splice donor region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000447.3 splice_donor, splice_donor_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN2 | NM_000447.3 | c.886+2_886+4del | splice_donor_variant, splice_donor_region_variant, intron_variant | ENST00000366783.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN2 | ENST00000366783.8 | c.886+2_886+4del | splice_donor_variant, splice_donor_region_variant, intron_variant | 5 | NM_000447.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457758Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 725462
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Alzheimer disease 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2017 | 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PSEN2 are known to be pathogenic (PMID: 18834536, 20375137, 24704512). This variant has not been reported in the literature in individuals with PSEN2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the PSEN2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at