rs186571865

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate 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:7
• Conservation: PhyloP100: 1.63

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2	c.616-6T>C		splice_region_variant, intron_variant	Intron 2 of 3	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000220676.2	c.616-6T>C		splice_region_variant, intron_variant	Intron 2 of 3	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1	c.616-6T>C		splice_region_variant, intron_variant	Intron 2 of 28	5		ENSP00000490104.1
RP1	ENST00000636932.1	c.616-6T>C		splice_region_variant, intron_variant	Intron 2 of 22	5		ENSP00000489857.1

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

GnomAD3 exomes AF: 0.00505 AC: 1269 AN: 251374 Hom.: 6 AF XY: 0.00481 AC XY: 654 AN XY: 135882

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 SAS exome AF: 0.000392

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

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00771

Gnomad4 ASJ exome AF: 0.00662

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00721

Gnomad4 OTH exome AF: 0.00560

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

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00688

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00588 Hom.: 2

Bravo AF: 0.00514

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RP1: BS1, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Benign:1

Dec 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 1 Benign:1

Oct 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.6
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

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