rs782344765

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_006915.3(RP2):c.8G>C(p.Cys3Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000926 in 1,166,907 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000098 ( 0 hom. 29 hem. )

Consequence

RP2
NM_006915.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.61

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

BS2

High Hemizygotes in GnomAdExome4 at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP2	NM_006915.3 link	c.8G>C	p.Cys3Ser	missense_variant	Exon 1 of 5	ENST00000218340.4	NP_008846.2	O75695A0A1B2JLU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4 link	c.8G>C	p.Cys3Ser	missense_variant	Exon 1 of 5	1	NM_006915.3	ENSP00000218340.3		O75695

Frequencies

GnomAD3 genomes

AF:

0.0000445

AC:

AN:

112270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34404

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000605

AC:

AN:

115651

Hom.:

AF XY:

0.0000734

AC XY:

AN XY:

40875

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000671

Gnomad OTH exome

AF:

0.000303

GnomAD4 exome

AF:

0.0000977

AC:

103

AN:

1054637

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

345043

show subpopulations

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:

0.000160

Gnomad4 FIN exome

AF:

0.0000531

Gnomad4 NFE exome

AF:

0.0000988

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000445

AC:

AN:

112270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34404

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000669

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RP2: PS4:Moderate, PP4, PS3:Supporting -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 20729296, 28209709, 20106869, 12037013, 22072390, 34906488, 23150612, 10942419, 20625056) -

Retinitis pigmentosa 2

Uncertain:1

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 2 (MIM# 312600). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (4 heterozygotes, 0 homozygotes, 3 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the N-terminal consensus myristoylation and palmitoylation motif where the cysteine-3 amino acid represents the site of palmitoylation (PMID 10942419, 12037013, Uniprot). (SP) 0803 - This variant has limited previous evidence of pathogenicity. This variant has previously been reported as likely pathogenic (ClinVar) and in a patient with X-linked retinitis pigmentosa (PMIDs: 20625056, 23150612). It has also been reported in the homozygous state in a female patient with HYAL deficiency where this variant was thought to explain the severity of this patient's ocular phenotype. However, this patient underwent exome sequencing at the laboratory who submitted the ClinVar entry; therefore it is unclear if this is an additional patient (PMID: 34906488). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function where this variant was shown to result in protein mislocalization (PMIDs: 10942419, 12037013, 22072390, 28209709, 20729296, 20106869). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Retinal dystrophy

Uncertain:1

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.86

Sift

Uncertain

0.017

Sift4G

Uncertain

0.038

Polyphen

0.99

Vest4

0.86

MutPred

0.40

Loss of catalytic residue at M1 (P = 0.0016);

MVP

0.98

MPC

1.0

ClinPred

0.79

GERP RS

3.7

Varity_R

0.83

gMVP

0.83

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

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