rs727504075
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_000283.4(PDE6B):c.2193+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,611,342 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_000283.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDE6B | NM_000283.4 | c.2193+1G>A | splice_donor_variant | ENST00000496514.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDE6B | ENST00000496514.6 | c.2193+1G>A | splice_donor_variant | 1 | NM_000283.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 251026Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135814
GnomAD4 exome AF: 0.000203 AC: 296AN: 1459112Hom.: 0 Cov.: 30 AF XY: 0.000180 AC XY: 131AN XY: 725994
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 08, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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 | Invitae | Jan 08, 2024 | This sequence change affects a donor splice site in intron 18 of the PDE6B 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 PDE6B are known to be pathogenic (PMID: 8394174, 8595886, 22334370). This variant is present in population databases (rs727504075, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with autosomal recessive retinitis pigmentosa or retinal dystrophy (PMID: 7724547, 25097241, 28041643, 28224992). It has also been observed to segregate with disease in related individuals. This variant is also known as a G>A transition at position 22624. ClinVar contains an entry for this variant (Variation ID: 167440). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 11, 2015 | The c.2193+1G>A variant in PDE6B has previously been reported in one individual with retinal dystrophy (Wang 2014) and in one individual with retinitis pigmento sa and was found to segregate with disease in an affected sibling (McLaughlin 19 95). All of these individuals were compound heterozygous. This variant has also been identified in 0.01% (9/66178) of European chromosomes by the Exome Aggregat ion Consortium (http://exac.broadinstitute.org/). Although this variant has bee n seen in the general population, its frequency is low enough to be consistent w ith a recessive carrier frequency. This variant occurs in the invariant region ( +/- 1/2) of the splice consensus sequence and is predicted to cause altered spli cing leading to an abnormal or absent protein. Complete loss of PDE6B function i s an established disease mechanism in retinitis pigmentosa. In summary, this var iant meets our criteria to be classified as pathogenic for retinitis pigmentosa in an autosomal recessive manner (www.partners.org/personalizedmedicine/lmm). - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The c.2193+1G>A variant in PDE6B was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
PDE6B-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 21, 2023 | PM3_Strong, PP1, PP3_Strong, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 20, 2023 | The PDE6B c.2193+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented causative for autosomal recessive retinitis pigmentosa (arRP) (McLaughlin et al. 1995 PubMed ID: 7724547; Wang et al. 2014. PubMed ID: 25097241). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-658734-G-A). Variants that disrupt the consensus splice donor site in PDE6B are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Retinitis pigmentosa 40 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The PDE6B c.2193+1G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. - |
Congenital stationary night blindness autosomal dominant 2;C3151107:Retinitis pigmentosa 40 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 16, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at