X-46837089-CGGGCTGGGACCAT-C

Position:

• chrX-46837089-CGGGCTGGGACCAT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006915.3(RP2):​c.-5_8del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RP2 NM_006915.3 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.14

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-46837089-CGGGCTGGGACCAT-C is Pathogenic according to our data. Variant chrX-46837089-CGGGCTGGGACCAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1384049.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP2	NM_006915.3	c.-5_8del		start_lost, 5_prime_UTR_variant	1/5	ENST00000218340.4	NP_008846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4	c.-5_8del		start_lost, 5_prime_UTR_variant	1/5	1	NM_006915.3	ENSP00000218340	P1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the initiator methionine in RP2. If translation initiates from the next in-frame methionine, the RP2 protein would no longer include the region containing the p.Gly2 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with RP2-related conditions (PMID: 16969763), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Disruption of the initiator codon has been observed in individual(s) with retinal dystrophy (PMID: 26355662, 29847639, Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the RP2 mRNA. The next in-frame methionine is located at codon 41. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-46696524;