rs61755786
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The ENST00000230381.7(PRPH2):βc.461_463delβ(p.Lys154del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
PRPH2
ENST00000230381.7 inframe_deletion
ENST00000230381.7 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.92
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000230381.7
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in ENST00000230381.7. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 6-42721871-GTCT-G is Pathogenic according to our data. Variant chr6-42721871-GTCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 13178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721871-GTCT-G is described in Lovd as [Pathogenic]. Variant chr6-42721871-GTCT-G is described in Lovd as [Likely_pathogenic]. Variant chr6-42721871-GTCT-G is described in Lovd as [Likely_pathogenic]. Variant chr6-42721871-GTCT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRPH2 | NM_000322.5 | c.461_463del | p.Lys154del | inframe_deletion | 1/3 | ENST00000230381.7 | NP_000313.2 | |
PRPH2 | XR_007059288.1 | n.724_726del | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRPH2 | ENST00000230381.7 | c.461_463del | p.Lys154del | inframe_deletion | 1/3 | 1 | NM_000322.5 | ENSP00000230381 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727248
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
Likely pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 21, 2021 | Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Andreas Laner, 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 | Nov 01, 1993 | - - |
Cone-rod dystrophy 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.461_463delAGA in the PRPH2 gene has been previously studied(PMIDs 8240110, 25412400, 27365499). 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 (rs61755786). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM2, PM4, PP1, PP5] and classified NM_000322.4:c.461_463delAGA in the PRPH2 gene as a Pathogenic mutation. - |
Patterned macular dystrophy 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1993 | - - |
PRPH2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This variant, c.461_463del, results in the deletion of 1 amino acid(s) of the PRPH2 protein (p.Lys154del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of inherited retinal disease (PMID: 8240110; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13178). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PRPH2 function (PMID: 27365499). This variant disrupts the p.Lys154 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been observed in individuals with PRPH2-related conditions (PMID: 26161267), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2020 | - - |
Stargardt disease 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.461_463delAGA in the PRPH2 gene has been previously studied(PMIDs 8240110, 25412400, 27365499). 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 (rs61755786). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM2, PM4, PP1, PP5] and classified NM_000322.4:c.461_463delAGA in the PRPH2 gene as a Pathogenic mutation. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at