X-46837114-TCTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_006915.3(RP2):c.16_18del(p.Ser6del) variant causes a inframe deletion 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RP2 NM_006915.3 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.27

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006915.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-46837114-TCTC-T is Pathogenic according to our data. Variant chrX-46837114-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10544.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-46837114-TCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP2	NM_006915.3	c.16_18del	p.Ser6del	inframe_deletion	1/5	ENST00000218340.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP2	ENST00000218340.4	c.16_18del	p.Ser6del	inframe_deletion	1/5	1	NM_006915.3	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

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects RP2 function (PMID: 10942419, 28209709). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 10544). This variant is also known as del Ser6, S6del, ∆Ser6, ∆S6. This variant has been observed in individuals with X-linked retinitis pigmentosa (PMID: 9697692, 10520237, 17724181, 30718709; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs137852284, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant, c.16_18del, results in the deletion of 1 amino acid(s) of the RP2 protein (p.Ser6del), but otherwise preserves the integrity of the reading frame. -

Retinitis pigmentosa 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 12, 2000

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852284; hg19: chrX-46696549;