rs79826315

Positions:

• chr4-625771-G-A
• chr4-625771-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000283.4(PDE6B):​c.145G>A​(p.Asp49Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. D49Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21240565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6B	NM_000283.4	c.145G>A	p.Asp49Asn	missense_variant	1/22	ENST00000496514.6	NP_000274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6B	ENST00000496514.6	c.145G>A	p.Asp49Asn	missense_variant	1/22	1	NM_000283.4	ENSP00000420295	P3
PDE6B	ENST00000255622.10	c.145G>A	p.Asp49Asn	missense_variant	1/22	1		ENSP00000255622	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461144 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.070	B;B
Vest4		0.19
MutPred		0.42		Gain of catalytic residue at D49 (P = 0.0278);Gain of catalytic residue at D49 (P = 0.0278);
MVP		0.82
MPC		0.13
ClinPred		0.63	D
GERP RS		5.0
Varity_R		0.12
gMVP		0.29

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: rs79826315; hg19: chr4-619560;