rs1805147

chrX-46860063-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006915.3(RP2):c.844C>T(p.Arg282Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,206,352 control chromosomes in the GnomAD database, including 343 homozygotes. There are 10,033 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (34 hom., 570 hem., cov: 23)
  • Exomes 𝑓: 0.027 (309 hom. 9463 hem.)
• Consequence: RP2 NM_006915.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.36

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053629577).
• BP6: Variant X-46860063-C-T is Benign according to our data. Variant chrX-46860063-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-46860063-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2136/111864) while in subpopulation NFE AF= 0.0303 (1609/53066). AF 95% confidence interval is 0.0291. There are 34 homozygotes in gnomad4. There are 570 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP2	NM_006915.3	c.844C>T	p.Arg282Trp	missense_variant	3/5	ENST00000218340.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP2	ENST00000218340.4	c.844C>T	p.Arg282Trp	missense_variant	3/5	1	NM_006915.3	P1

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2139 AN: 111808 Hom.: 34 Cov.: 23 AF XY: 0.0168 AC XY: 570 AN XY: 34004

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00876

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0223

Gnomad EAS AF: 0.000277

Gnomad SAS AF: 0.00510

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0184

GnomAD3 exomes AF: 0.0182 AC: 3337 AN: 182850 Hom.: 27 AF XY: 0.0170 AC XY: 1146 AN XY: 67332

Gnomad AFR exome AF: 0.00419

Gnomad AMR exome AF: 0.00822

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0273 AC: 29927 AN: 1094488 Hom.: 309 Cov.: 29 AF XY: 0.0263 AC XY: 9463 AN XY: 360050

Gnomad4 AFR exome AF: 0.00357

Gnomad4 AMR exome AF: 0.00833

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.0000995

Gnomad4 SAS exome AF: 0.00410

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0245

GnomAD4 genome AF: 0.0191 AC: 2136 AN: 111864 Hom.: 34 Cov.: 23 AF XY: 0.0167 AC XY: 570 AN XY: 34070

Gnomad4 AFR AF: 0.00443

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.0223

Gnomad4 EAS AF: 0.000278

Gnomad4 SAS AF: 0.00511

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0303

Gnomad4 OTH AF: 0.0182

Alfa AF: 0.0207 Hom.: 174

Bravo AF: 0.0176

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0291 AC: 84

ESP6500AA AF: 0.00365 AC: 14

ESP6500EA AF: 0.0328 AC: 221

ExAC AF: 0.0185 AC: 2241

EpiCase AF: 0.0301

EpiControl AF: 0.0288

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 235/10563=2.23% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: RP2 c.844C>T (p.Arg282Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.018 in 182850 control chromosomes, predominantly at a frequency of 0.03 within the Non-Finnish European subpopulation in the gnomAD database, including 25 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13.86 fold of the estimated maximal expected allele frequency for a pathogenic variant in RP2 causing Retinitis Pigmentosa, X-Linked phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	This variant is associated with the following publications: (PMID: 24265693, 11462235, 22995991, 25097241, 21738648, 27884173, 27535533, 10937588, 22334370, 11992260, 10862093) -

Retinitis pigmentosa 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Arg282Trp variant in RP2 has been identified in a Yugoslavian individual with retinitis pigmentosa (PMID: 11462235), but has also been identified in >2% of European (non-Finnish) chromosomes, 556 hemizygotes, and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for X-linked recessive retinitis pigmentosa. -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Benign	0.091	T
Sift4G	Uncertain	0.040	D
Polyphen		0.93	P
Vest4		0.048
MPC		0.38
ClinPred		0.017	T
GERP RS		3.4
Varity_R		0.23
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1805147; hg19: chrX-46719498; COSMIC: COSV99029197;