rs370898371

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000283.4(PDE6B):c.1107+3A>G variant causes a splice 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

PDE6B
NM_000283.4 splice_region, intron

Scores

Splicing: ADA: 0.9994

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 4.13

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]

PDE6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 4-656295-A-G is Pathogenic according to our data. Variant chr4-656295-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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	Protein	UniProt
PDE6B	NM_000283.4 linkuse as main transcript	c.1107+3A>G		splice_region_variant, intron_variant		ENST00000496514.6	NP_000274.3	P35913-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PDE6B	ENST00000496514.6 linkuse as main transcript	c.1107+3A>G	splice_region_variant, intron_variant	1	NM_000283.4	ENSP00000420295.1	P35913-1
PDE6B	ENST00000255622.10 linkuse as main transcript	c.1107+3A>G	splice_region_variant, intron_variant	1		ENSP00000255622.6	P35913-2
PDE6B	ENST00000429163.6 linkuse as main transcript	c.270+3A>G	splice_region_variant, intron_variant	2		ENSP00000406334.2	P35913-3
PDE6B	ENST00000487902.5 linkuse as main transcript	c.222+289A>G	intron_variant	3		ENSP00000418256.1	C9J7V6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251310

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000327

AC:

AN:

1378008

Hom.:

Cov.:

AF XY:

0.0000420

AC XY:

AN XY:

690602

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000406

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74398

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

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	Labcorp Genetics (formerly Invitae), Labcorp	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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 25, 2018	- -

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	- -

PDE6B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The PDE6B c.1107+3A>G variant is predicted to interfere with splicing. This variant is predicted to decrease the strength of the canonical donor splice site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant has been reported in the homozygous and compound heterozygous states in several individuals with retinitis pigmentosa (see for examples: Neveling et al. 2012. PubMed ID: 22334370; Karali et al. 2019. PubMed ID: 31877679; Martín-Sánchez et al. 2020. PubMed ID: 33302505). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic. -

Retinitis pigmentosa 40

Uncertain:1

Uncertain significance, flagged submission

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.61

Position offset: -3

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over