rs104894925

Positions:

• chrX-46837176-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006915.3(RP2):​c.76C>T​(p.Gln26Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: RP2 NM_006915.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.16

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 18 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 60 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-46837176-C-T is Pathogenic according to our data. Variant chrX-46837176-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-46837176-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP2	NM_006915.3	c.76C>T	p.Gln26Ter	stop_gained	1/5	ENST00000218340.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP2	ENST00000218340.4	c.76C>T	p.Gln26Ter	stop_gained	1/5	1	NM_006915.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1056868 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 345394

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 10545). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 9697692). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln26*) in the RP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RP2 are known to be pathogenic (PMID: 11992260, 20625056). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2018	The Q26X variant in the RP2 gene has been reported previously in an individual with X-linked retinitis pigmentosa (Schwahn et al., 1998). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q26X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Q26X as a pathogenic variant. -

Retinitis pigmentosa 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.76
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs104894925; hg19: chrX-46696611;