chr8-54629980-G-A

Position:

chr8-54629980-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000220676.2(RP1):c.6098G>A(p.Cys2033Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,544 control chromosomes in the GnomAD database, including 123,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2033F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 8434 hom., cov: 32)

Exomes 𝑓: 0.39 ( 115409 hom. )

Consequence

RP1
ENST00000220676.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.1454692E-4).

BP6

Variant 8-54629980-G-A is Benign according to our data. Variant chr8-54629980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54629980-G-A is described in Lovd as [Pathogenic]. Variant chr8-54629980-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1	NM_006269.2 linkuse as main transcript	c.6098G>A	p.Cys2033Tyr	missense_variant	4/4	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RP1	ENST00000220676.2 linkuse as main transcript	c.6098G>A	p.Cys2033Tyr	missense_variant	4/4	1	NM_006269.2	ENSP00000220676
RP1	ENST00000636932.1 linkuse as main transcript	c.787+7692G>A		intron_variant		5		ENSP00000489857
RP1	ENST00000637698.1 linkuse as main transcript	c.787+7692G>A		intron_variant		5		ENSP00000490104	P1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45965

AN:

151974

Hom.:

8431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.537

Gnomad EAS

AF:

0.0667

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.400

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.340

GnomAD3 exomes

AF:

0.335

AC:

84199

AN:

251054

Hom.:

16461

AF XY:

0.350

AC XY:

47510

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.529

Gnomad EAS exome

AF:

0.0606

Gnomad SAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.418

Gnomad OTH exome

AF:

0.394

GnomAD4 exome

AF:

0.387

AC:

566223

AN:

1461450

Hom.:

115409

Cov.:

AF XY:

0.389

AC XY:

282650

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.204

Gnomad4 ASJ exome

AF:

0.528

Gnomad4 EAS exome

AF:

0.0865

Gnomad4 SAS exome

AF:

0.344

Gnomad4 FIN exome

AF:

0.407

Gnomad4 NFE exome

AF:

0.413

Gnomad4 OTH exome

AF:

0.376

GnomAD4 genome

AF:

0.302

AC:

45970

AN:

152094

Hom.:

8434

Cov.:

AF XY:

0.301

AC XY:

22343

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.115

Gnomad4 AMR

AF:

0.256

Gnomad4 ASJ

AF:

0.537

Gnomad4 EAS

AF:

0.0668

Gnomad4 SAS

AF:

0.343

Gnomad4 FIN

AF:

0.400

Gnomad4 NFE

AF:

0.413

Gnomad4 OTH

AF:

0.336

Alfa

AF:

0.383

Hom.:

16142

Bravo

AF:

0.285

TwinsUK

AF:

0.423

AC:

1570

ALSPAC

AF:

0.408

AC:

1573

ESP6500AA

AF:

0.117

AC:

516

ESP6500EA

AF:

0.416

AC:

3577

ExAC

AF:

0.338

AC:

40983

Asia WGS

AF:

0.182

AC:

632

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	This variant is associated with the following publications: (PMID: 11864893, 11527933, 28418496) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

Retinitis pigmentosa 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.8

DANN

Benign

0.15

DEOGEN2

Benign

0.030

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.53

MetaRNN

Benign

0.00021

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.29

REVEL

Benign

0.056

Sift

Benign

0.81

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.049

MPC

0.039

ClinPred

0.010

GERP RS

0.40

Varity_R

0.068

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over