rs1805147

Positions:

chrX-46860063-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000218340.4(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
ENST00000218340.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.36

Variant links:

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]

RP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP2	NM_006915.3 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	3/5	ENST00000218340.4	NP_008846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	3/5	1	NM_006915.3	ENSP00000218340	P1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2139

AN:

111808

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

570

AN XY:

34004

show subpopulations

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.:

AF XY:

0.0170

AC XY:

1146

AN XY:

67332

show subpopulations

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.:

AF XY:

0.0263

AC XY:

9463

AN XY:

360050

show subpopulations

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.:

Cov.:

AF XY:

0.0167

AC XY:

570

AN XY:

34070

show subpopulations

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:

ESP6500AA

AF:

0.00365

AC:

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -
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% -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinitis pigmentosa 2

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.94

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.6

REVEL

Benign

0.21

Sift

Benign

0.091

Sift4G

Uncertain

0.040

Polyphen

0.93

Vest4

0.048

MPC

0.38

ClinPred

0.017

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

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