6-42721866-C-T

Variant names:

• chr6-42721866-C-T
• rs61755787
• NM_000322.5:c.469G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000322.5(PRPH2):​c.469G>A​(p.Asp157Asn) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D157Y) has been classified 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:8 O: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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42721866-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 6-42721866-C-T is Pathogenic according to our data. Variant chr6-42721866-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721866-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-42721866-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPH2	NM_000322.5	c.469G>A	p.Asp157Asn	missense_variant	Exon 1 of 3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1	n.732G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7	c.469G>A	p.Asp157Asn	missense_variant	Exon 1 of 3	1	NM_000322.5	ENSP00000230381.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal dystrophy Pathogenic:2

Jul 30, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. Comment: Variant observed de novo. -

Pigmentary retinal dystrophy Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

PRPH2-related disorder Pathogenic:1

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 157 of the PRPH2 protein (p.Asp157Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinal disease (PMID: 8994365, 17504850, 32531846; internal data). ClinVar contains an entry for this variant (Variation ID: 98671). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRPH2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Macular degeneration;C0344232:Blurred vision;C1862475:Abnormality of retinal pigmentation;C4551715:Pigmentary retinopathy Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1

Jan 07, 2020

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant NM_000322.4:c.469G>A in the PRPH2 gene has been previously studied(PMID 7875944). We found this variant in 2 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755787,CM951117). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3] and classified NM_000322.4:c.469G>A in the PRPH2 gene as a Likely Pathogenic mutation. -

Stargardt disease Pathogenic:1

Jan 07, 2020

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant NM_000322.4:c.469G>A in the PRPH2 gene has been previously studied(PMID 7875944). We found this variant in 2 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755787,CM951117). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3] and classified NM_000322.4:c.469G>A in the PRPH2 gene as a Likely Pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.53	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.88		Loss of ubiquitination at K154 (P = 0.0462);
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.95

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: rs61755787; hg19: chr6-42689604; COSMIC: COSV57837952;