rs587777694
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000313546.8(POC1B):c.810+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,447,824 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
ENST00000313546.8 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POC1B | NM_172240.3 | c.810+1G>T | splice_donor_variant | ENST00000313546.8 | NP_758440.1 | |||
POC1B | NM_001199777.2 | c.684+1G>T | splice_donor_variant | NP_001186706.1 | ||||
POC1B | NR_037659.2 | n.790+1G>T | splice_donor_variant, non_coding_transcript_variant | |||||
POC1B | NR_037660.2 | n.849+1G>T | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POC1B | ENST00000313546.8 | c.810+1G>T | splice_donor_variant | 1 | NM_172240.3 | ENSP00000323302 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000527 AC: 8AN: 151750Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000265 AC: 6AN: 226694Hom.: 0 AF XY: 0.0000486 AC XY: 6AN XY: 123554
GnomAD4 exome AF: 0.000110 AC: 142AN: 1296074Hom.: 0 Cov.: 28 AF XY: 0.0000972 AC XY: 62AN XY: 637744
GnomAD4 genome AF: 0.0000527 AC: 8AN: 151750Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74126
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2023 | Observed with another POC1B variant in multiple unrelated patients with progressive retinopathy referred for genetic testing at GeneDx and in published literature (PMID: 25018096, 34065499); Published functional studies demonstrate a damaging effect with skipping of exon 7 or exons 6 and 7 resulting in a null allele (PMID: 25018096); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34065499, 25018096) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change affects a donor splice site in intron 7 of the POC1B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587777694, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with POC1B related conditions (PMID: 25018096, 34065499). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 155771). Studies have shown that disruption of this splice site results in skipping of exon 6 and skipping of exon 6-7 and introduces a premature termination codon (PMID: 25018096). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Cone-rod dystrophy 20 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 07, 2014 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at