rs186571865

Variant names:

• chr8-54622111-T-C
• rs186571865
• NM_006269.2:c.616-6T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006269.2(RP1):​c.616-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,614,088 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (36 hom.)
• Consequence: RP1 NM_006269.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002528
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: 1.63
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
• RP1-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• RP1-related dominant retinopathy

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-54622111-T-C is Benign according to our data. Variant chr8-54622111-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00443 (674/152302) while in subpopulation AMR AF = 0.00713 (109/15298). AF 95% confidence interval is 0.00637. There are 5 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD,SD gene

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.616-6T>C		splice_region intron	N/A	NP_006260.1	P56715
	RP1	NM_001375654.1		c.616-6T>C		splice_region 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.616-6T>C		splice_region intron	N/A	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.616-6T>C		splice_region intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.616-6T>C		splice_region intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152184 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00687

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00505 AC: 1269 AN: 251374 AF XY: 0.00481

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00747

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00625 AC: 9132 AN: 1461786 Hom.: 36 Cov.: 32 AF XY: 0.00600 AC XY: 4366 AN XY: 727196

African (AFR) AF: 0.00128 AC: 43 AN: 33478

American (AMR) AF: 0.00771 AC: 345 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 173 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86252

European-Finnish (FIN) AF: 0.00176 AC: 94 AN: 53418

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5756

European-Non Finnish (NFE) AF: 0.00721 AC: 8019 AN: 1111942

Other (OTH) AF: 0.00560 AC: 338 AN: 60390

GnomAD4 genome AF: 0.00443 AC: 674 AN: 152302 Hom.: 5 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74478

African (AFR) AF: 0.00130 AC: 54 AN: 41580

American (AMR) AF: 0.00713 AC: 109 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00688 AC: 468 AN: 68012

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00567 Hom.: 3

Bravo AF: 0.00514

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00818

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
1	-	1	Retinitis pigmentosa (2)
-	-	1	Retinitis pigmentosa 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.6
DANN	Benign	0.91
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs186571865; hg19: chr8-55534671; COSMIC: COSV55120718;