4-625652-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000283.4(PDE6B):c.26G>A(p.Arg9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,613,764 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (6 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029651225).
• BP6: Variant 4-625652-G-A is Benign according to our data. Variant chr4-625652-G-A is described in ClinVar as [Benign]. Clinvar id is 784032.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-625652-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00505 (769/152338) while in subpopulation AFR AF= 0.0173 (718/41572). AF 95% confidence interval is 0.0162. There are 7 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6B	NM_000283.4	c.26G>A	p.Arg9Gln	missense_variant	1/22	ENST00000496514.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6B	ENST00000496514.6	c.26G>A	p.Arg9Gln	missense_variant	1/22	1	NM_000283.4	P3
PDE6B	ENST00000255622.10	c.26G>A	p.Arg9Gln	missense_variant	1/22	1		A1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 769 AN: 152220 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00144 AC: 360 AN: 249450 Hom.: 6 AF XY: 0.00103 AC XY: 139 AN XY: 135020

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000805

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000565 AC: 826 AN: 1461426 Hom.: 6 Cov.: 32 AF XY: 0.000497 AC XY: 361 AN XY: 727040

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00505 AC: 769 AN: 152338 Hom.: 7 Cov.: 33 AF XY: 0.00460 AC XY: 343 AN XY: 74504

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00126 Hom.: 6

Bravo AF: 0.00621

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00176 AC: 214

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	11
Dann	Uncertain	0.99
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.034
Sift	Benign	0.072	T;T
Sift4G	Uncertain	0.031	D;D
Polyphen		0.0010	B;B
Vest4		0.036
MVP		0.70
MPC		0.15
ClinPred		0.012	T
GERP RS		2.9
Varity_R		0.032
gMVP		0.15

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: rs76755568; hg19: chr4-619441;