chrX-46837089-CGGGCTGGGACCAT-C

Position:

• chrX-46837089-CGGGCTGGGACCAT-C

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.-5_8delGGACCATGGGCTG​(p.Met1fs) variant causes a frameshift, start lost 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 frameshift, start_lost
• 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 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-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_8delGGACCATGGGCTG	p.Met1fs	frameshift_variant, start_lost	1/5	ENST00000218340.4	NP_008846.2
RP2	NM_006915.3	c.-5_8delGGACCATGGGCTG		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_8delGGACCATGGGCTG	p.Met1fs	frameshift_variant, start_lost	1/5	1	NM_006915.3	ENSP00000218340.3
RP2	ENST00000218340	c.-5_8delGGACCATGGGCTG		5_prime_UTR_variant	1/5	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

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. 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 (ExAC no frequency). 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. -

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;