rs28933687

Positions:

• chrX-46853726-G-A
• chrX-46853726-G-C
• chrX-46853726-G-T

Variant summary

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

The NM_006915.3(RP2):​c.353G>A​(p.Arg118His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,250 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: RP2 NM_006915.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.45

Genes affected

RP2 (HGNC:10274): (RP2 activator of ARL3 GTPase) The RP2 locus has been implicated as one cause of X-linked retinitis pigmentosa. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. Progressive retinal degeneration may therefore be due to the accumulation of incorrectly-folded photoreceptor or neuron-specific tubulin isoforms followed by progressive cell death [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain C-CAP/cofactor C-like (size 155) in uniprot entity XRP2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_006915.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-46853726-G-A is Pathogenic according to our data. Variant chrX-46853726-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-46853726-G-A is described in Lovd as [Pathogenic]. Variant chrX-46853726-G-A is described in Lovd as [Pathogenic]. Variant chrX-46853726-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-46853726-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP2	NM_006915.3	c.353G>A	p.Arg118His	missense_variant	2/5	ENST00000218340.4	NP_008846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4	c.353G>A	p.Arg118His	missense_variant	2/5	1	NM_006915.3	ENSP00000218340.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098250 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RP2 function (PMID: 10942419, 16472755, 18376416, 21738648, 22072390, 28209709). ClinVar contains an entry for this variant (Variation ID: 10546). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 9697692, 10090907, 10520237, 12657579, 20021257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 118 of the RP2 protein (p.Arg118His). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Retinitis pigmentosa 2 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2000	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.98		Loss of MoRF binding (P = 0.0696);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.89

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: rs28933687; hg19: chrX-46713161; COSMIC: COSV54461662;