chrX-46837098-ACCATGGGCTGCTTCTTCTC-A

Variant names:

• chrX-46837098-ACCATGGGCTGCTTCTTCTC-A
• NM_006915.3:c.-1_18delCATGGGCTGCTTCTTCTCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006915.3(RP2):​c.-1_18delCATGGGCTGCTTCTTCTCC​(p.Met1fs) variant causes a frameshift, start lost change. 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 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.61

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-46837098-ACCATGGGCTGCTTCTTCTC-A is Pathogenic according to our data. Variant chrX-46837098-ACCATGGGCTGCTTCTTCTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2728412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP2	NM_006915.3	c.-1_18delCATGGGCTGCTTCTTCTCC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 5	ENST00000218340.4	NP_008846.2
RP2	NM_006915.3	c.-1_18delCATGGGCTGCTTCTTCTCC		5_prime_UTR_variant	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.-1_18delCATGGGCTGCTTCTTCTCC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 5	1	NM_006915.3	ENSP00000218340.3
RP2	ENST00000218340	c.-1_18delCATGGGCTGCTTCTTCTCC		5_prime_UTR_variant	Exon 1 of 5	1	NM_006915.3	ENSP00000218340.3

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

May 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This variant has not been reported in the literature in individuals affected with RP2-related conditions. -

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-46696533;