rs121918562

chr6-42704534-CGTG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM4_Supporting PP3 PP5

The NM_000322.5(PRPH2):c.656_658del(p.Pro219del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (no stars). 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 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2 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 Uncertain_significance. Variant got 5 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
• PM4: Nonframeshift variant in NON repetitive region in NM_000322.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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 no_assertion_criteria_provided, 0 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/exons	MANE	UniProt
PRPH2	NM_000322.5	c.656_658del	p.Pro219del	inframe_deletion	2/3	ENST00000230381.7
PRPH2	XR_007059288.1	n.1101_1103del		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7	c.656_658del	p.Pro219del	inframe_deletion	2/3	1	NM_000322.5	P1

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 06, 2021	Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters. -
not provided, no classification provided	literature only	Retina International	-	- -

Retinitis pigmentosa 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 1991

- -

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;