NM_000283.4:c.1485dupG

Variant names:

• chr4-660481-A-AG
• rs1360937549
• NM_000283.4:c.1485dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000283.4(PDE6B):​c.1485dupG​(p.Pro496AlafsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDE6B NM_000283.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.83
• Publications: 1 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 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 40

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• congenital stationary night blindness autosomal dominant 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-660481-A-AG is Pathogenic according to our data. Variant chr4-660481-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 438189.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1485dupG	p.Pro496AlafsTer5	frameshift	Exon 12 of 22	NP_000274.3	P35913-1
	PDE6B	NM_001440547.1		c.1485dupG	p.Pro496AlafsTer5	frameshift	Exon 12 of 22	NP_001427476.1
	PDE6B	NM_001145291.2		c.1485dupG	p.Pro496AlafsTer5	frameshift	Exon 12 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.1485dupG	p.Pro496AlafsTer5	frameshift	Exon 12 of 22	ENSP00000420295.1	P35913-1
	PDE6B	ENST00000255622.10	TSL:1	c.1485dupG	p.Pro496AlafsTer5	frameshift	Exon 12 of 22	ENSP00000255622.6	P35913-2
	PDE6B	ENST00000429163.6	TSL:2	c.648dupG	p.Pro217AlafsTer5	frameshift	Exon 10 of 20	ENSP00000406334.2	P35913-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461382 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111732

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs1360937549; hg19: chr4-654270;