X-46837142-GT-G

Variant names:

• chrX-46837142-GT-G
• rs1556313474
• NM_006915.3:c.43delT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006915.3(RP2):​c.43delT​(p.Ser15ArgfsTer31) variant causes a frameshift 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: RP2 NM_006915.3 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0460
• Publications: 0 publications found

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]

RP2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• RP2-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 131 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-46837142-GT-G is Pathogenic according to our data. Variant chrX-46837142-GT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 437945.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006915.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP2	NM_006915.3	MANE Select	c.43delT	p.Ser15ArgfsTer31	frameshift	Exon 1 of 5	NP_008846.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP2	ENST00000218340.4	TSL:1 MANE Select	c.43delT	p.Ser15ArgfsTer31	frameshift	Exon 1 of 5	ENSP00000218340.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.46e-7 AC: 1 AN: 1057079 Hom.: 0 Cov.: 30 AF XY: 0.00000289 AC XY: 1 AN XY: 345719

African (AFR) AF: 0.00 AC: 0 AN: 25019

American (AMR) AF: 0.00 AC: 0 AN: 28391

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18672

East Asian (EAS) AF: 0.00 AC: 0 AN: 27330

South Asian (SAS) AF: 0.00 AC: 0 AN: 49989

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37825

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 821233

Other (OTH) AF: 0.00 AC: 0 AN: 44529

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Abnormality of the eye Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Undetermined rare ocular disorder with frequency of less than eight patients

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.046
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556313474; hg19: chrX-46696577;