rs2274321

Variant names:

Variant summary

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

The NM_000329.3(RPE65):c.643+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,358 control chromosomes in the GnomAD database, including 1,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 137 hom., cov: 32)

Exomes 𝑓: 0.025 ( 1031 hom. )

Consequence

RPE65
NM_000329.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.352

Variant links:

Genes affected

RPE65 (HGNC:10294): (retinoid isomerohydrolase RPE65) The protein encoded by this gene is a component of the vitamin A visual cycle of the retina which supplies the 11-cis retinal chromophore of the photoreceptors opsin visual pigments. It is a member of the carotenoid cleavage oxygenase superfamily. All members of this superfamily are non-heme iron oxygenases with a seven-bladed propeller fold and oxidatively cleave carotenoid carbon:carbon double bonds. However, the protein encoded by this gene has acquired a divergent function that involves the concerted O-alkyl ester cleavage of its all-trans retinyl ester substrate and all-trans to 11-cis double bond isomerization of the retinyl moiety. As such, it performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Mutations in this gene are associated with early-onset severe blinding disorders such as Leber congenital. [provided by RefSeq, Oct 2017]

RPE65 links:

LOC124904198 (HGNC:):

LOC124904198 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 (BayesDel_noAF=-0.59).

BP6

Variant 1-68440831-G-A is Benign according to our data. Variant chr1-68440831-G-A is described in ClinVar as [Benign]. Clinvar id is 255838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPE65	NM_000329.3 link	c.643+22C>T		intron_variant	Intron 6 of 13	ENST00000262340.6	NP_000320.1	Q16518

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6 link	c.643+22C>T		intron_variant	Intron 6 of 13	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4931

AN:

152126

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0605

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.0444

Gnomad EAS

AF:

0.0247

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0296

GnomAD3 exomes

AF:

0.0324

AC:

8127

AN:

250972

Hom.:

298

AF XY:

0.0364

AC XY:

4939

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.0622

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.0438

Gnomad EAS exome

AF:

0.0150

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0188

Gnomad OTH exome

AF:

0.0266

GnomAD4 exome

AF:

0.0253

AC:

37001

AN:

1461114

Hom.:

1031

Cov.:

AF XY:

0.0282

AC XY:

20491

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.0637

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0408

Gnomad4 EAS exome

AF:

0.0251

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0162

Gnomad4 NFE exome

AF:

0.0178

Gnomad4 OTH exome

AF:

0.0284

GnomAD4 genome

AF:

0.0325

AC:

4941

AN:

152244

Hom.:

137

Cov.:

AF XY:

0.0336

AC XY:

2497

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0605

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.0444

Gnomad4 EAS

AF:

0.0247

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.0157

Gnomad4 NFE

AF:

0.0170

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.0271

Hom.:

Bravo

AF:

0.0322

Asia WGS

AF:

0.0580

AC:

200

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 87 with choroidal involvement

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 2

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: 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

-0.59

CADD

Benign

9.4

DANN

Benign

0.79

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