6-42722221-TC-T

Position:

• chr6-42722221-TC-T

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.113del​(p.Gly38AspfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPH2 NM_000322.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.50

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 6-42722221-TC-T is Pathogenic according to our data. Variant chr6-42722221-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 13177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42722221-TC-T is described in Lovd as [Pathogenic]. Variant chr6-42722221-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH2	NM_000322.5	c.113del	p.Gly38AspfsTer4	frameshift_variant	1/3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1	n.376del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7	c.113del	p.Gly38AspfsTer4	frameshift_variant	1/3	1	NM_000322.5	ENSP00000230381	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 06, 2021	Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12566026, 32531846, 32037395) -

Vitelliform macular dystrophy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

PRPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Gly38Aspfs*4) 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 adult-onset foveomacular dystrophy (PMID: 12566026). This variant is also known as c.112delG. ClinVar contains an entry for this variant (Variation ID: 13177). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 07, 2019

- -

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.113delG in the PRPH2 gene has been previously studied (PMID 12566026). We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755769,CD030391). It is absent in gnomAD browser. It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PVS1, PM2, PP1-S] and classified NM_000322.4:c.113delG in the PRPH2 gene as a Pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs61755769; hg19: chr6-42689959;