rs144562730

chr4-653934-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_000283.4(PDE6B):c.794G>A(p.Arg265Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 9.58

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-AS1 (HGNC:40438): (PDE6B antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000283.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.16307157).
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6B	NM_000283.4	c.794G>A	p.Arg265Gln	missense_variant	4/22	ENST00000496514.6
PDE6B-AS1	NR_183810.1	n.157C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6B	ENST00000496514.6	c.794G>A	p.Arg265Gln	missense_variant	4/22	1	NM_000283.4	P3
PDE6B-AS1	ENST00000468356.3	n.1319C>T		non_coding_transcript_exon_variant	3/4	1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00111 AC: 279 AN: 251060 Hom.: 2 AF XY: 0.00132 AC XY: 179 AN XY: 135844

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00108 AC: 1581 AN: 1461472 Hom.: 5 Cov.: 32 AF XY: 0.00115 AC XY: 839 AN XY: 727056

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74482

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000831

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PDE6B p.Arg265Gln variant was identified in a compound heterozygous patient with retinitis pigmentosa from a cohort of 99 patients with inherited retinal dystrophies and 21 healthy relatives (Bernardis_2016_PMID:28127548). The variant was identified in dbSNP (ID: rs144562730) and ClinVar (classified as likely benign by Illumina and uncertain significance by EGL Genetics). The variant was identified in control databases in 302 of 282448 chromosomes (2 homozygous) at a frequency of 0.001069 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 70 of 30614 chromosomes (freq: 0.002287), European (non-Finnish) in 193 of 128836 chromosomes (freq: 0.001498), Other in 7 of 7214 chromosomes (freq: 0.00097), Latino in 22 of 35436 chromosomes (freq: 0.000621), Ashkenazi Jewish in 4 of 10352 chromosomes (freq: 0.000386), African in 5 of 24930 chromosomes (freq: 0.000201) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Arg265 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital stationary night blindness autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.16	T;T
Sift4G	Benign	0.31	T;T
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.91
MPC		0.64
ClinPred		0.042	T
GERP RS		5.3
Varity_R		0.26
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144562730; hg19: chr4-647723; COSMIC: COSV55325890; COSMIC: COSV55325890;