chr8-54620970-AGT-A

Position:

• chr8-54620970-AGT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006269.2(RP1):​c.6_7del​(p.Ser2ArgfsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RP1 NM_006269.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.22

Genes affected

RP1 (HGNC:10263): (RP1 axonemal microtubule associated) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 324 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-54620970-AGT-A is Pathogenic according to our data. Variant chr8-54620970-AGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 2500819.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-54620970-AGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP1	NM_006269.2	c.6_7del	p.Ser2ArgfsTer16	frameshift_variant	2/4	ENST00000220676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP1	ENST00000220676.2	c.6_7del	p.Ser2ArgfsTer16	frameshift_variant	2/4	1	NM_006269.2
RP1	ENST00000636932.1	c.6_7del	p.Ser2ArgfsTer16	frameshift_variant	2/23	5
RP1	ENST00000637698.1	c.6_7del	p.Ser2ArgfsTer16	frameshift_variant	2/29	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Pangenia Genomics, Pangenia Inc.

Mar 14, 2022

The RP1, c.6_7delTG (p.Ser2Argfs*16) variant is a frameshift variant in exon 2 of RP1 gene, resulting in a premature translation stop signal in the mRNA predicted to undergo nonsense mediated decay, creating a null variant of the RP1 gene. This variant is absent from controls in population database. There is presence of co-segregation with disease in multiple affected family members. This variant is detected in trans with a likely-pathogenic variant [RP1, c.4941dupT (p.Pro1648Serfs*13)]. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-55533530;