8-54628953-T-C

Variant names:

• chr8-54628953-T-C
• rs414352
• NM_006269.2:c.5071T>C

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.5071T>C​(p.Ser1691Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,824 control chromosomes in the GnomAD database, including 60,729 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5376 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55353 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0640
• Publications: 49 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=1.4066696E-4).
• BP6: Variant 8-54628953-T-C is Benign according to our data. Variant chr8-54628953-T-C is described in ClinVar as Benign. ClinVar VariationId is 95354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 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.5071T>C	p.Ser1691Pro	missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+6665T>C		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.5071T>C	p.Ser1691Pro	missense	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+6665T>C		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+6665T>C		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39081 AN: 151890 Hom.: 5366 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.277 AC: 69748 AN: 251360 AF XY: 0.275

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.272 AC: 397874 AN: 1461818 Hom.: 55353 Cov.: 59 AF XY: 0.271 AC XY: 197185 AN XY: 727208

African (AFR) AF: 0.193 AC: 6456 AN: 33480

American (AMR) AF: 0.329 AC: 14707 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6125 AN: 26134

East Asian (EAS) AF: 0.405 AC: 16092 AN: 39698

South Asian (SAS) AF: 0.245 AC: 21093 AN: 86258

European-Finnish (FIN) AF: 0.215 AC: 11499 AN: 53412

Middle Eastern (MID) AF: 0.305 AC: 1759 AN: 5768

European-Non Finnish (NFE) AF: 0.273 AC: 303635 AN: 1111952

Other (OTH) AF: 0.273 AC: 16508 AN: 60392

GnomAD4 genome AF: 0.257 AC: 39123 AN: 152006 Hom.: 5376 Cov.: 32 AF XY: 0.257 AC XY: 19090 AN XY: 74300

African (AFR) AF: 0.193 AC: 7993 AN: 41464

American (AMR) AF: 0.348 AC: 5309 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 810 AN: 3470

East Asian (EAS) AF: 0.421 AC: 2171 AN: 5154

South Asian (SAS) AF: 0.245 AC: 1180 AN: 4812

European-Finnish (FIN) AF: 0.214 AC: 2255 AN: 10558

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18489 AN: 67972

Other (OTH) AF: 0.295 AC: 623 AN: 2114

Alfa AF: 0.270 Hom.: 13307

Bravo AF: 0.265

TwinsUK AF: 0.275 AC: 1018

ALSPAC AF: 0.265 AC: 1020

ESP6500AA AF: 0.200 AC: 883

ESP6500EA AF: 0.272 AC: 2341

ExAC AF: 0.272 AC: 33062

Asia WGS AF: 0.331 AC: 1150 AN: 3478

EpiCase AF: 0.280

EpiControl AF: 0.278

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (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	0.057
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.064
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.053
Sift	Benign	0.43	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.032
ClinPred		0.0024	T
GERP RS		3.7
Varity_R		0.085
gMVP		0.079
Mutation Taster		=96/4	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: rs414352; hg19: chr8-55541513; COSMIC: COSV55122639;