Genetic Variant PDE6B:p.Thr251Arg (chr4-653892-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000283.4(PDE6B):c.752C>G(p.Thr251Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T251M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PDE6B
NM_000283.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.58

Publications

0 publications found

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:

PDE6B-AS1 (HGNC:40438): (PDE6B antisense RNA 1)

PDE6B-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000283.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE6B	NM_000283.4	MANE Select	c.752C>G	p.Thr251Arg	missense	Exon 4 of 22	NP_000274.3	P35913-1
PDE6B	NM_001440547.1		c.752C>G	p.Thr251Arg	missense	Exon 4 of 22	NP_001427476.1
PDE6B	NM_001145291.2		c.752C>G	p.Thr251Arg	missense	Exon 4 of 22	NP_001138763.2	P35913-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE6B	ENST00000496514.6	TSL:1 MANE Select	c.752C>G	p.Thr251Arg	missense	Exon 4 of 22	ENSP00000420295.1	P35913-1
PDE6B	ENST00000255622.10	TSL:1	c.752C>G	p.Thr251Arg	missense	Exon 4 of 22	ENSP00000255622.6	P35913-2
PDE6B	ENST00000467152.1	TSL:1	n.150C>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.5

PhyloP100

7.6

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.89

MutPred

0.40

Gain of helix (P = 0.005)

MVP

0.95

MPC

0.63

ClinPred

1.0

GERP RS

5.3

Varity_R

0.82

gMVP

0.73

Mutation Taster

=26/74

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over