4-653914-C-G

Position:

• chr4-653914-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000283.4(PDE6B):​c.774C>G​(p.His258Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H258N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.87

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain GAF 2 (size 177) in uniprot entity PDE6B_HUMAN there are 19 pathogenic changes around while only 1 benign (95%) in NM_000283.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-653912-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant 4-653914-C-G is Pathogenic according to our data. Variant chr4-653914-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 865778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6B	NM_000283.4	c.774C>G	p.His258Gln	missense_variant	4/22	ENST00000496514.6	NP_000274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6B	ENST00000496514.6	c.774C>G	p.His258Gln	missense_variant	4/22	1	NM_000283.4	ENSP00000420295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.069	T;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.66		Loss of ubiquitination at K259 (P = 0.0877);Loss of ubiquitination at K259 (P = 0.0877);
MVP		0.94
MPC		0.60
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.78
gMVP		0.51

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: rs1735848896; hg19: chr4-647703;