rs370898371
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5
The NM_000283.4(PDE6B):c.1107+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000032 in 1,530,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
PDE6B
NM_000283.4 splice_donor_region, intron
NM_000283.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9994
2
Clinical Significance
Conservation
PhyloP100: 4.13
Genes affected
PDE6B (HGNC:8786): (phosphodiesterase 6B) Photon absorption triggers a signaling cascade in rod photoreceptors that activates cGMP phosphodiesterase (PDE), resulting in the rapid hydrolysis of cGMP, closure of cGMP-gated cation channels, and hyperpolarization of the cell. PDE is a peripheral membrane heterotrimeric enzyme made up of alpha, beta, and gamma subunits. This gene encodes the beta subunit. Mutations in this gene result in retinitis pigmentosa and autosomal dominant congenital stationary night blindness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 4-656295-A-G is Pathogenic according to our data. Variant chr4-656295-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438188.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}. Variant chr4-656295-A-G is described in Lovd as [Likely_pathogenic]. Variant chr4-656295-A-G is described in Lovd as [Pathogenic]. Variant chr4-656295-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDE6B | NM_000283.4 | c.1107+3A>G | splice_donor_region_variant, intron_variant | ENST00000496514.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDE6B | ENST00000496514.6 | c.1107+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_000283.4 | P3 | |||
PDE6B | ENST00000255622.10 | c.1107+3A>G | splice_donor_region_variant, intron_variant | 1 | A1 | ||||
PDE6B | ENST00000429163.6 | c.270+3A>G | splice_donor_region_variant, intron_variant | 2 | |||||
PDE6B | ENST00000487902.5 | c.222+289A>G | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152270Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251310Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135880
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GnomAD4 exome AF: 0.0000327 AC: 45AN: 1378008Hom.: 0 Cov.: 23 AF XY: 0.0000420 AC XY: 29AN XY: 690602
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely 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 | Dec 05, 2023 | This sequence change falls in intron 8 of the PDE6B gene. It does not directly change the encoded amino acid sequence of the PDE6B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370898371, gnomAD 0.009%). This variant has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 22334370, 28041643, 30718709; Invitae). ClinVar contains an entry for this variant (Variation ID: 438188). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2021 | In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported as likely pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000780789.2; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33576794, 32581362, 30718709, 31877679, 28041643, 30998820, 25999674, 22334370) - |
Retinitis pigmentosa Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 25, 2018 | - - |
Retinitis pigmentosa 40 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 25, 2020 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PS4_MOD. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at