NM_000283.4:c.2193+1G>A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000283.4(PDE6B):c.2193+1G>A variant causes a splice donor, intron 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, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
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:6
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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. -
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: 7724547, 32531858, 25097241, 25525159, 28224992, 30998820, 31980526, 33302505, 31589614, 32037395, 36284670, 37510321, 31964843, 36819107, 34906470, 38219857, 32581362) -
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Retinitis pigmentosa Pathogenic:4
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). -
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. -
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PDE6B-related disorder Pathogenic:2
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. Variants that disrupt the consensus splice donor site in PDE6B are expected to be pathogenic. This variant is interpreted as pathogenic. -
PM3_Strong, PP1, PP3_Strong, PM2 -
Retinitis pigmentosa 40 Pathogenic:2
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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
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Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at