rs61730895

chr10-84257984-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001012720.2(RGR):c.722C>T(p.Ser241Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,614,066 control chromosomes in the GnomAD database, including 1,868 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (180 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1688 hom.)
• Consequence: RGR NM_001012720.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.47

Genes affected

RGR (HGNC:9990): (retinal G protein coupled receptor) This gene encodes a putative retinal G-protein coupled receptor. The gene is a member of the opsin subfamily of the 7 transmembrane, G-protein coupled receptor 1 family. Like other opsins which bind retinaldehyde, it contains a conserved lysine residue in the seventh transmembrane domain. The protein acts as a photoisomerase to catalyze the conversion of all-trans-retinal to 11-cis-retinal. The reverse isomerization occurs with rhodopsin in retinal photoreceptor cells. The protein is exclusively expressed in tissue adjacent to retinal photoreceptor cells, the retinal pigment epithelium and Mueller cells. This gene may be associated with autosomal recessive and autosomal dominant retinitis pigmentosa (arRP and adRP, respectively). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017181933).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGR	NM_001012720.2	c.722C>T	p.Ser241Phe	missense_variant	6/7	ENST00000652092.2
RGR	NM_002921.4	c.734C>T	p.Ser245Phe	missense_variant	6/7
RGR	NM_001012722.2	c.631-524C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGR	ENST00000652092.2	c.722C>T	p.Ser241Phe	missense_variant	6/7		NM_001012720.2	A1

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6042 AN: 152182 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0524 AC: 13161 AN: 251384 Hom.: 430 AF XY: 0.0524 AC XY: 7122 AN XY: 135862

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.0829

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.0655

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0393

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0444 AC: 64882 AN: 1461764 Hom.: 1688 Cov.: 32 AF XY: 0.0453 AC XY: 32966 AN XY: 727192

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.0811

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.0692

Gnomad4 FIN exome AF: 0.0339

Gnomad4 NFE exome AF: 0.0402

Gnomad4 OTH exome AF: 0.0454

GnomAD4 genome AF: 0.0397 AC: 6041 AN: 152302 Hom.: 180 Cov.: 32 AF XY: 0.0413 AC XY: 3076 AN XY: 74474

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.0710

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.0677

Gnomad4 FIN AF: 0.0305

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0373 Hom.: 67

Bravo AF: 0.0411

TwinsUK AF: 0.0421 AC: 156

ALSPAC AF: 0.0366 AC: 141

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.0353 AC: 304

ExAC AF: 0.0506 AC: 6148

Asia WGS AF: 0.0860 AC: 298 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0375

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -

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

Mar 06, 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	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.59
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.10
Sift	Benign	0.71	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.13
ClinPred		0.0019	T
GERP RS		-0.63
gMVP		0.095

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

Other links and lift over

dbSNP: rs61730895; hg19: chr10-86017740; COSMIC: COSV63894899; COSMIC: COSV63894899;