chr4-625917-C-A

Variant names:

• chr4-625917-C-A
• rs876657718
• NM_000283.4:c.291C>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000283.4(PDE6B):​c.291C>A​(p.Tyr97*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000966 in 1,449,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: PDE6B NM_000283.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.59
• 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):

• retinitis pigmentosa 40

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 4-625917-C-A is Pathogenic according to our data. Variant chr4-625917-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 228390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6B	NM_000283.4	c.291C>A	p.Tyr97*	stop_gained	Exon 1 of 22	ENST00000496514.6	NP_000274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6B	ENST00000496514.6	c.291C>A	p.Tyr97*	stop_gained	Exon 1 of 22	1	NM_000283.4	ENSP00000420295.1
PDE6B	ENST00000255622.10	c.291C>A	p.Tyr97*	stop_gained	Exon 1 of 22	1		ENSP00000255622.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000904 AC: 2 AN: 221222 AF XY: 0.00000826

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: 0.0000205

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000966 AC: 14 AN: 1449040 Hom.: 0 Cov.: 33 AF XY: 0.0000125 AC XY: 9 AN XY: 719940

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.00 AC: 0 AN: 42754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.00 AC: 0 AN: 84734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1106564

Other (OTH) AF: 0.0000167 AC: 1 AN: 59886

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr97*) in the PDE6B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDE6B are known to be pathogenic (PMID: 8394174, 8595886, 22334370). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive inherited retinal disease (PMID: 27208204). ClinVar contains an entry for this variant (Variation ID: 228390). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

-

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1

Mar 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr97X variant in PDE6B has not been previously reported in individuals wi th retinitis pigmentosa and was absent from large population studies. This nonse nse variant leads to a premature termination codon at position 97, which is pred icted to lead to a truncated or absent protein. Complete loss of PDE6B function is an established disease mechanism in retinitis pigmentosa. In summary, this va riant meets our criteria to be classified as pathogenic for retinitis pigmentosa in an autosomal recessive manner (www.partners.org/personalizedmedicine/lmm). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.6
Vest4		0.65
GERP RS		4.1
PromoterAI		0.0096	Neutral
Mutation Taster		=0/200	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: rs876657718; hg19: chr4-619706;