rs62640590

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.905G>C(p.Cys302Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,200,366 control chromosomes in the GnomAD database, including 2 homozygotes. There are 234 hemizygotes in GnomAD. In-silico tool predicts 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. C302Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., 110 hem., cov: 23)

Exomes 𝑓: 0.00044 ( 1 hom. 124 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.38

Publications

10 publications found

Variant links:

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

RPGR Gene-Disease associations (from GenCC):

retinitis pigmentosa 3
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
RPGR-related retinopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
primary ciliary dyskinesia-retinitis pigmentosa syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
macular degeneration, X-linked atrophic
Inheritance: XL Classification: LIMITED Submitted by: G2P

RPGR links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-38304664-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 98810.

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.024760395).

BP6

Variant X-38304664-C-G is Benign according to our data. Variant chrX-38304664-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (374/111891) while in subpopulation AFR AF = 0.0115 (354/30836). AF 95% confidence interval is 0.0105. There are 1 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 374 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.905G>C	p.Cys302Ser	missense_variant	Exon 8 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 link	c.905G>C	p.Cys302Ser	missense_variant	Exon 8 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1 link	c.172-361457C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

373

AN:

111837

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000668

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00603

GnomAD2 exomes

AF:

0.000989

AC:

180

AN:

181930

AF XY:

0.000734

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000741

Gnomad OTH exome

AF:

0.000892

GnomAD4 exome

AF:

0.000441

AC:

480

AN:

1088475

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

124

AN XY:

354841

show subpopulations

African (AFR)

AF:

0.0122

AC:

321

AN:

26211

American (AMR)

AF:

0.000739

AC:

AN:

35188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19320

East Asian (EAS)

AF:

0.00

AC:

AN:

30141

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.000247

AC:

AN:

4045

European-Non Finnish (NFE)

AF:

0.000109

AC:

AN:

833458

Other (OTH)

AF:

0.000874

AC:

AN:

45743

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00334

AC:

374

AN:

111891

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

110

AN XY:

34109

show subpopulations

African (AFR)

AF:

0.0115

AC:

354

AN:

30836

American (AMR)

AF:

0.000667

AC:

AN:

10493

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2705

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53226

Other (OTH)

AF:

0.00596

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000759

Hom.:

Bravo

AF:

0.00377

TwinsUK

AF:

0.00

AC:

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RPGR: PM5, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

Jul 13, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RPGR c.905G>C (p.Cys302Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 181930 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote and 49 hemizygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGR causing X-linked Retinitis Pigmentosa (0.012 vs. 0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although c.905G>C has been reported in the literature in at least two individuals affected with Retinitis Pigmentosa (e.g. Wang_2014, Costa_2017), these reports do not provide unequivocal conclusions about association of the variant with X-linked Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary ciliary dyskinesia

Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;D;.;.;.;.;.;.

LIST_S2

Benign

0.0

.;T;T;T;T;.;T;T;T

MetaRNN

Benign

0.025

T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.1

M;M;M;.;M;M;M;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.1

D;.;D;.;.;.;D;.;.

Sift

Pathogenic

0.0

D;.;D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;.;.;D;.;.

Vest4

0.88

ClinPred

0.12

GERP RS

5.3

PromoterAI

0.013

Neutral

(source)

Varity_R

0.88

gMVP

0.98

Mutation Taster

=7/93

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over