rs786205579

Positions:

• chr6-42721838-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000322.5(PRPH2):​c.497G>A​(p.Cys166Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPH2 NM_000322.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.81

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 16 ACMG points.

• PM1: In a topological_domain Lumenal (size 140) in uniprot entity PRPH2_HUMAN there are 250 pathogenic changes around while only 6 benign (98%) in NM_000322.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 6-42721838-C-T is Pathogenic according to our data. Variant chr6-42721838-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721838-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH2	NM_000322.5	c.497G>A	p.Cys166Tyr	missense_variant	1/3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1	n.760G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7	c.497G>A	p.Cys166Tyr	missense_variant	1/3	1	NM_000322.5	ENSP00000230381	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 29, 2021	Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

PRPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2022

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PRPH2 protein function. ClinVar contains an entry for this variant (Variation ID: 191208). This missense change has been observed in individuals with PRPH2-related conditions (PMID: 26061163, 26355662; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 166 of the PRPH2 protein (p.Cys166Tyr). -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.87		Gain of ubiquitination at K164 (P = 0.0941);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.99

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: rs786205579; hg19: chr6-42689576;