chrX-46837102-T-C

Variant names:

• chrX-46837102-T-C
• rs797044561
• NM_006915.3:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_006915.3(RP2):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RP2 NM_006915.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.68
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• RP2-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 29 pathogenic variants. Next in-frame start position is after 41 codons. Genomic position: 46853494. Lost 0.115 part of the original CDS.
• PS1: Another start lost variant in NM_006915.3 (RP2) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-46837102-T-C is Pathogenic according to our data. Variant chrX-46837102-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 191246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP2	NM_006915.3	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENST00000218340.4	NP_008846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	1	NM_006915.3	ENSP00000218340.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the RP2 mRNA. The next in-frame methionine is located at codon 41. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with retinitis pigmentosa (PMID: 26355662, 29847639). ClinVar contains an entry for this variant (Variation ID: 191246). This variant disrupts a region of the RP2 protein in which other variant(s) (p.Ser6del) have been determined to be pathogenic (PMID: 9697692, 10942419, 17724181, 28209709; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

X-linked retinitis pigmentosa Pathogenic:1

Sep 10, 2015

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinitis pigmentosa Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.76	D
PhyloP100		3.7
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Gain of phosphorylation at M1 (P = 0.0469);
MVP		0.97
ClinPred		0.99	D
GERP RS		3.5
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.84
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044561; hg19: chrX-46696537;