rs104894082

Variant names:

• chr8-54625911-C-T
• rs104894082
• NM_006269.2:c.2029C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-54625911-C-T
• chr8-54625911-C-A
• chr8-54625911-C-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006269.2(RP1):​c.2029C>T​(p.Arg677*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RP1 NM_006269.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 0.783
• Publications: 46 publications found

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]

RP1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Illumina
• RP1-related dominant retinopathy

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• RP1-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 217 pathogenic variants in the truncated region.
• PP5: Variant 8-54625911-C-T is Pathogenic according to our data. Variant chr8-54625911-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006269.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1	NM_006269.2	MANE Select	c.2029C>T	p.Arg677*	stop_gained	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+3623C>T		intron	N/A	NP_001362583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1	ENST00000220676.2	TSL:1 MANE Select	c.2029C>T	p.Arg677*	stop_gained	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+3623C>T		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+3623C>T		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461606 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000189 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
6	-	-	Retinitis pigmentosa 1 (6)
3	-	-	Retinal dystrophy (3)
1	-	-	RP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.70	D
PhyloP100		0.78
Vest4		0.79
GERP RS		4.8
Mutation Taster		=0/200	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: rs104894082; hg19: chr8-55538471; COSMIC: COSV55128917;