4-625771-G-T

Position:

chr4-625771-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000283.4(PDE6B):c.145G>T(p.Asp49Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,613,498 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 12 hom. )

Consequence

PDE6B
NM_000283.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.99

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007756084).

BP6

Variant 4-625771-G-T is Benign according to our data. Variant chr4-625771-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 138644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-625771-G-T is described in Lovd as [Benign]. Variant chr4-625771-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (197/152354) while in subpopulation EAS AF= 0.0292 (151/5178). AF 95% confidence interval is 0.0254. There are 5 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6B	NM_000283.4 link	c.145G>T	p.Asp49Tyr	missense_variant	1/22	ENST00000496514.6	NP_000274.3	P35913-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6B	ENST00000496514.6 link	c.145G>T	p.Asp49Tyr	missense_variant	1/22	1	NM_000283.4	ENSP00000420295.1		P35913-1
PDE6B	ENST00000255622.10 link	c.145G>T	p.Asp49Tyr	missense_variant	1/22	1		ENSP00000255622.6		P35913-2

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

189

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0289

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00280

AC:

699

AN:

249576

Hom.:

AF XY:

0.00260

AC XY:

351

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0322

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.000517

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.000978

AC:

1429

AN:

1461144

Hom.:

Cov.:

AF XY:

0.000973

AC XY:

707

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0269

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.000852

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00129

AC:

197

AN:

152354

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0292

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00181

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00315

AC:

382

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2011

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

Jan 13, 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. -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

.;D

Eigen

Benign

-0.014

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.0

L;L

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.62

P;P

Vest4

0.28

MVP

0.81

MPC

0.28

ClinPred

0.043

GERP RS

5.0

Varity_R

0.37

gMVP

0.50

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