rs61755783

Positions:

chr6-42721911-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000322.5(PRPH2):c.424C>T(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 1.81

Variant links:

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]

PRPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-42721910-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418424.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 6-42721911-G-A is Pathogenic according to our data. Variant chr6-42721911-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721911-G-A is described in Lovd as [Pathogenic]. Variant chr6-42721911-G-A is described in Lovd as [Pathogenic]. Variant chr6-42721911-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5 linkuse as main transcript	c.424C>T	p.Arg142Trp	missense_variant	1/3	ENST00000230381.7
PRPH2	XR_007059288.1 linkuse as main transcript	n.687C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7 linkuse as main transcript	c.424C>T	p.Arg142Trp	missense_variant	1/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251422

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000404

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2023	Considered a founder variant in individuals from the southeastern region of the Netherlands (Boon et al., 2009); Identified in individuals with autosomal dominant retinitis pigmentosa (Neveling et al., 2012; Van Cauwenbergh et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29555955, 34411390, 19243827, 34647987, 34828423, 23891399, 8644804, 22003107, 22334370, 28076437, 17653047, 11139263, 11801511, 19038374, 30910914, 31047497, 30215852, 29155698, 28559085, 30718709, 31456290, 32531846, 31589614, 33846575, 34906036, 33546218) -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 14, 2021	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, Johan den Dunnen, Kornelia Neveling, LOVD, Manon Peeters. Comment: Variant observed de novo. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Patterned macular dystrophy 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	Apr 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 15, 2022	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 27, 2019	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Stargardt disease

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	Jan 07, 2020	The variant NM_000322.4:c.424C>T in the PRPH2 gene has been previously studied(PMIDs 7875944, 22003107, 22334370, 28559085, 28076437, 29555955, 29155698, 30215852, 30910914). We found this variant in 5 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755783,CM951116). It is present in gnomAD browser (AF 0.0000163). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.424C>T in the PRPH2 gene as a Pathogenic mutation. -
Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	Dec 13, 2022	- -

Progressive cone dystrophy (without rod involvement)

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Patterned dystrophy of the retinal pigment epithelium

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.424C>T in the PRPH2 gene has been previously studied(PMIDs 7875944, 22003107, 22334370, 28559085, 28076437, 29555955, 29155698, 30215852, 30910914). We found this variant in 5 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755783,CM951116). It is present in gnomAD browser (AF 0.0000163). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.424C>T in the PRPH2 gene as a Pathogenic mutation. -

Choroidal dystrophy, central areolar 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1996

- -

PRPH2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 142 of the PRPH2 protein (p.Arg142Trp). This variant is present in population databases (rs61755783, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant pattern dystrophy, mild central areolarchoroidal dystrophy, or other retinal disease (PMID: 8644804, 19038374, 19243827, 28076437, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13183). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRPH2 protein function. For these reasons, this variant has been classified as Pathogenic. -

maculopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Cone dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Sep 01, 2016

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Jan 07, 2020

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.23

MutationTaster

Benign

0.93

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.84

MutPred

0.65

Loss of disorder (P = 0.0165);

MVP

0.92

MPC

0.98

ClinPred

0.97

GERP RS

1.9

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over