4-635913-T-C

Variant names:

• chr4-635913-T-C
• rs62295357
• NM_000283.4:c.655T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 40

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• congenital stationary night blindness autosomal dominant 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 92769.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00455 (694/152378) while in subpopulation NFE AF = 0.00811 (552/68040). AF 95% confidence interval is 0.00755. There are 8 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000283.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	NM_000283.4	MANE Select	c.655T>C	p.Tyr219His	missense	Exon 3 of 22	NP_000274.3
	PDE6B	NM_001440547.1		c.655T>C	p.Tyr219His	missense	Exon 3 of 22	NP_001427476.1
	PDE6B	NM_001145291.2		c.655T>C	p.Tyr219His	missense	Exon 3 of 22	NP_001138763.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	ENST00000496514.6	TSL:1 MANE Select	c.655T>C	p.Tyr219His	missense	Exon 3 of 22	ENSP00000420295.1
	PDE6B	ENST00000255622.10	TSL:1	c.655T>C	p.Tyr219His	missense	Exon 3 of 22	ENSP00000255622.6

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

GnomAD2 exomes AF: 0.00441 AC: 1108 AN: 251448 AF XY: 0.00474

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 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

African (AFR) AF: 0.00123 AC: 41 AN: 33314

American (AMR) AF: 0.00188 AC: 84 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00355 AC: 306 AN: 86086

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53418

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.00820 AC: 9053 AN: 1104658

Other (OTH) AF: 0.00518 AC: 311 AN: 60080

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

African (AFR) AF: 0.00151 AC: 63 AN: 41596

American (AMR) AF: 0.00281 AC: 43 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00811 AC: 552 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00641 Hom.: 10

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

Jan 29, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDE6B: BS2

Retinitis pigmentosa Uncertain:1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Feb 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.36
Sift	Benign	0.54	T
Sift4G	Benign	0.54	T
Polyphen		0.020	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
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs62295357; hg19: chr4-629702;