rs121918562

Variant names:

• chr6-42704534-CGTG-C
• rs61755807
• NM_000322.5:c.656_658delCAC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000322.5(PRPH2):​c.656_658delCAC​(p.Pro219del) variant causes a disruptive inframe deletion 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P219P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRPH2 NM_000322.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 9.93

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000322.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000322.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-42704534-CGTG-C is Pathogenic according to our data. Variant chr6-42704534-CGTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98697.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-42704534-CGTG-C is described in Lovd as [Likely_pathogenic]. Variant chr6-42704534-CGTG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPH2	NM_000322.5	c.656_658delCAC	p.Pro219del	disruptive_inframe_deletion	Exon 2 of 3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1	n.1101_1103delCAC		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7	c.656_658delCAC	p.Pro219del	disruptive_inframe_deletion	Exon 2 of 3	1	NM_000322.5	ENSP00000230381.5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2 Other:1

Jan 30, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1684223, 9331261, 26773759, 34411390) -

Apr 06, 2021

Leiden Open Variation Database

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Retinitis pigmentosa 7 Pathogenic:1

Dec 12, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs61755807; hg19: chr6-42672272;