rs1554270834

chr6-42722068-GGCTGGGTC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000322.5(PRPH2):c.259_266del(p.Asp87GlnfsTer87) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,892 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PRPH2 NM_000322.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.82

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 18 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 6-42722068-GGCTGGGTC-G is Pathogenic according to our data. Variant chr6-42722068-GGCTGGGTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 437964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42722068-GGCTGGGTC-G is described in Lovd as [Pathogenic]. Variant chr6-42722068-GGCTGGGTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5	c.259_266del	p.Asp87GlnfsTer87	frameshift_variant	1/3	ENST00000230381.7
PRPH2	XR_007059288.1	n.522_529del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7	c.259_266del	p.Asp87GlnfsTer87	frameshift_variant	1/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

Jul 31, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 437964). This premature translational stop signal has been observed in individual(s) with autosomal dominant PRPH2-related conditions (PMID: 24608669, 28041643, 32531846, 32581362). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp87Glnfs*87) 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). -

Retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Stargardt disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Jan 07, 2020

The variant NM_000322.4:c.259_266delGACCCAGC in the PRPH2 gene has been previously studied (PMIDs 24608669, 28041643). We found this variant in 2 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (CD143729). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PVS1, PS4, PM2, PP5] and classified NM_000322.4:c.259_266delGACCCAGC in the PRPH2 gene as a Pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554270834; hg19: chr6-42689806;