8-54629980-G-A

Variant names:

• chr8-54629980-G-A
• rs61739567
• NM_006269.2:c.6098G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006269.2(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. 15/21 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 NM_006269.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00
• Publications: 37 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 95357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

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.6098G>A	p.Cys2033Tyr	missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+7692G>A		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.6098G>A	p.Cys2033Tyr	missense	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+7692G>A		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+7692G>A		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45965 AN: 151974 Hom.: 8431 Cov.: 32

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

GnomAD2 exomes AF: 0.335 AC: 84199 AN: 251054 AF XY: 0.350

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 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.: 52 AF XY: 0.389 AC XY: 282650 AN XY: 727026

African (AFR) AF: 0.113 AC: 3776 AN: 33466

American (AMR) AF: 0.204 AC: 9106 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 13786 AN: 26128

East Asian (EAS) AF: 0.0865 AC: 3431 AN: 39650

South Asian (SAS) AF: 0.344 AC: 29656 AN: 86244

European-Finnish (FIN) AF: 0.407 AC: 21726 AN: 53390

Middle Eastern (MID) AF: 0.466 AC: 2687 AN: 5764

European-Non Finnish (NFE) AF: 0.413 AC: 459352 AN: 1111708

Other (OTH) AF: 0.376 AC: 22703 AN: 60380

GnomAD4 genome AF: 0.302 AC: 45970 AN: 152094 Hom.: 8434 Cov.: 32 AF XY: 0.301 AC XY: 22343 AN XY: 74338

African (AFR) AF: 0.115 AC: 4784 AN: 41536

American (AMR) AF: 0.256 AC: 3908 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1861 AN: 3466

East Asian (EAS) AF: 0.0668 AC: 346 AN: 5178

South Asian (SAS) AF: 0.343 AC: 1650 AN: 4808

European-Finnish (FIN) AF: 0.400 AC: 4224 AN: 10558

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28034 AN: 67950

Other (OTH) AF: 0.336 AC: 710 AN: 2114

Alfa AF: 0.374 Hom.: 35642

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.8
DANN	Benign	0.15
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00021	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.056
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.049
MPC		0.039
ClinPred		0.010	T
GERP RS		0.40
Varity_R		0.068
gMVP		0.29
Mutation Taster		=98/2	polymorphism (auto)

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: rs61739567; hg19: chr8-55542540; COSMIC: COSV55112031;