rs121918564

Positions:

• chr6-42704419-G-C
• chr6-42704419-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000322.5(PRPH2):​c.774C>G​(p.Tyr258Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y258Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRPH2 NM_000322.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.46

Genes affected

PRPH2 (HGNC:9942): (peripherin 2) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis. Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 71 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-42704419-G-C is Pathogenic according to our data. Variant chr6-42704419-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1175302.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-42704419-G-C is described in Lovd as [Pathogenic]. Variant chr6-42704419-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5	c.774C>G	p.Tyr258Ter	stop_gained	2/3	ENST00000230381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7	c.774C>G	p.Tyr258Ter	stop_gained	2/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Apr 06, 2021

Curator: Global Variome, with Curator vacancy. Submitters to LOVD: LOVD, Manon Peeters. -

PRPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Tyr258*) in the PRPH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRPH2 are known to be pathogenic (PMID: 8111389, 8485575, 8485576, 8675410, 16916875, 17504850, 22863181, 25675413, 26061163, 27365499, 29555955, 33546218). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophy (PMID: 29555955). ClinVar contains an entry for this variant (Variation ID: 1175302). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.90
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42672157;