rs370898371

Variant names:

• chr4-656295-A-G
• rs370898371
• NM_000283.4:c.1107+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-656295-A-G
• chr4-656295-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000283.4(PDE6B):​c.1107+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000032 in 1,530,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PDE6B NM_000283.4 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 4.13
• Publications: 6 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: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-656295-A-G is Pathogenic according to our data. Variant chr4-656295-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1107+3A>G		splice_region intron	N/A	NP_000274.3	P35913-1
	PDE6B	NM_001440547.1		c.1107+3A>G		splice_region intron	N/A	NP_001427476.1
	PDE6B	NM_001145291.2		c.1107+3A>G		splice_region intron	N/A	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.1107+3A>G		splice_region intron	N/A	ENSP00000420295.1	P35913-1
	PDE6B	ENST00000255622.10	TSL:1	c.1107+3A>G		splice_region intron	N/A	ENSP00000255622.6	P35913-2
	PDE6B	ENST00000429163.6	TSL:2	c.270+3A>G		splice_region intron	N/A	ENSP00000406334.2	P35913-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152270 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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251310 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000327 AC: 45 AN: 1378008 Hom.: 0 Cov.: 23 AF XY: 0.0000420 AC XY: 29 AN XY: 690602

African (AFR) AF: 0.00 AC: 0 AN: 31890

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84604

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.0000406 AC: 42 AN: 1035646

Other (OTH) AF: 0.0000174 AC: 1 AN: 57530

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000929 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
2	-	-	Retinal dystrophy (2)
2	-	-	Retinitis pigmentosa (2)
1	-	-	PDE6B-related disorder (1)
-	1	-	Retinitis pigmentosa 40 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.95
PhyloP100		4.1
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370898371; hg19: chr4-650084;