rs10902758

Variant names:

• chr4-654854-G-A
• rs10902758
• NM_000283.4:c.958G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000283.4(PDE6B):​c.958G>A​(p.Val320Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,579,676 control chromosomes in the GnomAD database, including 789,598 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 1.0 (76020 hom., cov: 32)
  • Exomes 𝑓: 1.0 (713578 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.61
• Publications: 33 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.386741E-7).
• BP6: Variant 4-654854-G-A is Benign according to our data. Variant chr4-654854-G-A is described in ClinVar as Benign. ClinVar VariationId is 167436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	NM_000283.4	MANE Select	c.958G>A	p.Val320Ile	missense	Exon 6 of 22	NP_000274.3	P35913-1
	PDE6B	NM_001440547.1		c.958G>A	p.Val320Ile	missense	Exon 6 of 22	NP_001427476.1
	PDE6B	NM_001145291.2		c.958G>A	p.Val320Ile	missense	Exon 6 of 22	NP_001138763.2	P35913-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6B	ENST00000496514.6	TSL:1 MANE Select	c.958G>A	p.Val320Ile	missense	Exon 6 of 22	ENSP00000420295.1	P35913-1
	PDE6B	ENST00000255622.10	TSL:1	c.958G>A	p.Val320Ile	missense	Exon 6 of 22	ENSP00000255622.6	P35913-2
	PDE6B-AS1	ENST00000468356.3	TSL:1	n.1132+228C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.999 AC: 152029 AN: 152138 Hom.: 75960 Cov.: 32

Gnomad AFR AF: 0.997

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 251298 AN: 251346 AF XY: 1.00

Gnomad AFR exome AF: 0.997

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1427287 AN: 1427420 Hom.: 713578 Cov.: 33 AF XY: 1.00 AC XY: 712057 AN XY: 712116

African (AFR) AF: 0.997 AC: 32793 AN: 32882

American (AMR) AF: 1.00 AC: 44697 AN: 44700

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25884 AN: 25884

East Asian (EAS) AF: 1.00 AC: 39560 AN: 39560

South Asian (SAS) AF: 1.00 AC: 85578 AN: 85578

European-Finnish (FIN) AF: 1.00 AC: 53330 AN: 53330

Middle Eastern (MID) AF: 0.999 AC: 5703 AN: 5708

European-Non Finnish (NFE) AF: 1.00 AC: 1080522 AN: 1080538

Other (OTH) AF: 1.00 AC: 59220 AN: 59240

GnomAD4 genome AF: 0.999 AC: 152148 AN: 152256 Hom.: 76020 Cov.: 32 AF XY: 0.999 AC XY: 74384 AN XY: 74438

African (AFR) AF: 0.997 AC: 41423 AN: 41530

American (AMR) AF: 1.00 AC: 15303 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5158 AN: 5158

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68022 AN: 68022

Other (OTH) AF: 1.00 AC: 2110 AN: 2110

Alfa AF: 1.00 Hom.: 141532

Bravo AF: 0.999

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.997 AC: 4392

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 1.00 AC: 121377

Asia WGS AF: 0.999 AC: 3476 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital stationary night blindness autosomal dominant 2 (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 40 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.85
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	N
PhyloP100		2.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.10
ClinPred		0.0036	T
GERP RS		4.7
Varity_R		0.024
gMVP		0.089
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10902758; hg19: chr4-648643; COSMIC: COSV55329070; COSMIC: COSV55329070;