rs62295357

chr4-635913-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000283.4(PDE6B):c.655T>C(p.Tyr219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,606,172 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (44 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.98

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015854329).
• BP6: Variant 4-635913-T-C is Benign according to our data. Variant chr4-635913-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92769.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, Uncertain_significance=1}. Variant chr4-635913-T-C is described in Lovd as [Likely_benign]. Variant chr4-635913-T-C is described in Lovd as [Benign]. Variant chr4-635913-T-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00681 (9895/1453794) while in subpopulation NFE AF= 0.0082 (9053/1104658). AF 95% confidence interval is 0.00805. There are 44 homozygotes in gnomad4_exome. There are 4863 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6B	NM_000283.4	c.655T>C	p.Tyr219His	missense_variant	3/22	ENST00000496514.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6B	ENST00000496514.6	c.655T>C	p.Tyr219His	missense_variant	3/22	1	NM_000283.4	P3
PDE6B	ENST00000255622.10	c.655T>C	p.Tyr219His	missense_variant	3/22	1		A1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152260 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00811

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00441 AC: 1108 AN: 251448 Hom.: 3 AF XY: 0.00474 AC XY: 644 AN XY: 135916

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00372

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00758

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00681 AC: 9895 AN: 1453794 Hom.: 44 Cov.: 29 AF XY: 0.00672 AC XY: 4863 AN XY: 723822

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00355

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00820

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.00455 AC: 694 AN: 152378 Hom.: 8 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74510

Gnomad4 AFR AF: 0.00151

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00811

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00685 Hom.: 5

Bravo AF: 0.00456

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00456 AC: 553

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PDE6B: BS2 -

Retinitis pigmentosa Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital stationary night blindness autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	10
Dann	Benign	0.18
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.41	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.54	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.020	B;B
Vest4		0.68
MVP		0.48
MPC		0.23
ClinPred		0.0011	T
GERP RS		1.6
Varity_R		0.042
gMVP		0.58

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: rs62295357; hg19: chr4-629702;