10-87709196-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_ModeratePP5_Moderate
The NM_001015880.2(PAPSS2):c.28G>T(p.Glu10Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,599,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001015880.2 stop_gained, splice_region
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 |
---|---|---|---|---|---|---|---|
PAPSS2 | NM_001015880.2 | c.28G>T | p.Glu10Ter | stop_gained, splice_region_variant | 2/13 | ENST00000456849.2 | |
PAPSS2 | NM_004670.4 | c.28G>T | p.Glu10Ter | stop_gained, splice_region_variant | 2/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAPSS2 | ENST00000456849.2 | c.28G>T | p.Glu10Ter | stop_gained, splice_region_variant | 2/13 | 1 | NM_001015880.2 | A1 | |
PAPSS2 | ENST00000361175.8 | c.28G>T | p.Glu10Ter | stop_gained, splice_region_variant | 2/12 | 1 | P4 | ||
PAPSS2 | ENST00000465996.5 | n.50G>T | splice_region_variant, non_coding_transcript_exon_variant | 2/3 | 2 | ||||
PAPSS2 | ENST00000482258.1 | n.71G>T | splice_region_variant, non_coding_transcript_exon_variant | 2/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1447854Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1AN XY: 721312
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74280
ClinVar
Submissions by phenotype
Spondyloepimetaphyseal dysplasia, PAPSS2 type Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2023 | This sequence change creates a premature translational stop signal (p.Glu10*) in the PAPSS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAPSS2 are known to be pathogenic (PMID: 22791835, 23633440). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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. This variant has not been reported in the literature in individuals affected with PAPSS2-related conditions. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at