rs28675771

Positions:

• chr4-670119-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001350154.3(PDE6B):​c.1675A>G​(p.Met559Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,610,026 control chromosomes in the GnomAD database, including 329,275 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26789 hom., cov: 34)
  • Exomes 𝑓: 0.64 (302486 hom.)
• Consequence: PDE6B NM_001350154.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.47

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-670119-A-G is Benign according to our data. Variant chr4-670119-A-G is described in ClinVar as [Benign]. Clinvar id is 349400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-670119-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6B	NM_000283.4	c.*12A>G		3_prime_UTR_variant	22/22	ENST00000496514.6	NP_000274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6B	ENST00000496514.6	c.*12A>G		3_prime_UTR_variant	22/22	1	NM_000283.4	ENSP00000420295.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88823 AN: 151942 Hom.: 26767 Cov.: 34

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.575

GnomAD3 exomes AF: 0.615 AC: 154433 AN: 251034 Hom.: 48351 AF XY: 0.621 AC XY: 84320 AN XY: 135740

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.535

Gnomad EAS exome AF: 0.426

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.678

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.641 AC: 935064 AN: 1457966 Hom.: 302486 Cov.: 33 AF XY: 0.643 AC XY: 466429 AN XY: 725460

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.617

Gnomad4 ASJ exome AF: 0.537

Gnomad4 EAS exome AF: 0.404

Gnomad4 SAS exome AF: 0.652

Gnomad4 FIN exome AF: 0.676

Gnomad4 NFE exome AF: 0.659

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.585 AC: 88886 AN: 152060 Hom.: 26789 Cov.: 34 AF XY: 0.584 AC XY: 43398 AN XY: 74312

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.679

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.571

Alfa AF: 0.641 Hom.: 31904

Bravo AF: 0.568

Asia WGS AF: 0.522 AC: 1818 AN: 3478

EpiCase AF: 0.648

EpiControl AF: 0.660

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Congenital stationary night blindness autosomal dominant 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Retinitis pigmentosa 40 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Retinitis pigmentosa 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.31
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs28675771; hg19: chr4-663908; COSMIC: COSV55324901; COSMIC: COSV55324901;