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

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

PDE6B
NM_000283.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.52
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 4-664945-G-A is Pathogenic according to our data. Variant chr4-664945-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 167440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-664945-G-A is described in Lovd as [Pathogenic]. Variant chr4-664945-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-664945-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PDE6BNM_000283.4 linkc.2193+1G>A splice_donor_variant, intron_variant Intron 18 of 21 ENST00000496514.6 NP_000274.3 P35913-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PDE6BENST00000496514.6 linkc.2193+1G>A splice_donor_variant, intron_variant Intron 18 of 21 1 NM_000283.4 ENSP00000420295.1 P35913-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000717
AC:
18
AN:
251026
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135814
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000203
AC:
296
AN:
1459112
Hom.:
0
Cov.:
30
AF XY:
0.000180
AC XY:
131
AN XY:
725994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000262
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000162
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Oct 08, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 18, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:4
Mar 11, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Apr 01, 2021
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

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. -

Apr 01, 2018
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

PDE6B-related disorder Pathogenic:2
Aug 05, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Aug 21, 2023
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3_Strong, PP1, PP3_Strong, PM2 -

Retinitis pigmentosa 40 Pathogenic:2
Sep 01, 2016
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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
Sep 07, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:1
Aug 16, 2018
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.71
Position offset: 28
DS_DL_spliceai
0.97
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727504075; hg19: chr4-658734; API