rs62295357

Positions:

chr4-635913-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000496514.6(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
ENST00000496514.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.98

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 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, Uncertain_significance=1, Likely_benign=2}. 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 GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6B	NM_000283.4 linkuse as main transcript	c.655T>C	p.Tyr219His	missense_variant	3/22	ENST00000496514.6	NP_000274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6B	ENST00000496514.6 linkuse as main transcript	c.655T>C	p.Tyr219His	missense_variant	3/22	1	NM_000283.4	ENSP00000420295	P3	P35913-1
PDE6B	ENST00000255622.10 linkuse as main transcript	c.655T>C	p.Tyr219His	missense_variant	3/22	1		ENSP00000255622	A1	P35913-2

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

694

AN:

152260

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00474

AC XY:

644

AN XY:

135916

show subpopulations

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.:

Cov.:

AF XY:

0.00672

AC XY:

4863

AN XY:

723822

show subpopulations

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.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74510

show subpopulations

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.:

Bravo

AF:

0.00456

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00456

AC:

553

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

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 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

Retinitis pigmentosa

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

not specified

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2014	- -

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

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.18

DEOGEN2

Benign

0.25

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.59

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

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

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