rs2274321

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). The gene RPE65 is included in the ClinGen Criteria Specification Registry.

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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Leber congenital amaurosis 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
RPE65-related recessive retinopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
RPE65-related dominant retinopathy
Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
retinitis pigmentosa 20
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe early-childhood-onset retinal dystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa 87 with choroidal involvement
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RPE65 links:

LOC124904198 (HGNC:):

LOC124904198 links:

Genome browser will be placed here

ACMG classification

Specifications for RPE65 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPE65	NM_000329.3	MANE Select	c.643+22C>T	intron	N/A	NP_000320.1	Q16518
RPE65	NM_001406853.1		c.535+22C>T	intron	N/A	NP_001393782.1
RPE65	NM_001406856.1		c.367+22C>T	intron	N/A	NP_001393785.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPE65	ENST00000262340.6	TSL:1 MANE Select	c.643+22C>T	intron	N/A	ENSP00000262340.5	Q16518
RPE65	ENST00000713936.1		n.*548+22C>T	intron	N/A	ENSP00000519233.1	A0AAQ5BH58
RPE65	ENST00000713937.1		n.643+22C>T	intron	N/A	ENSP00000519234.1	A0AAQ5BH46

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

GnomAD2 exomes

AF:

0.0324

AC:

8127

AN:

250972

AF XY:

0.0364

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 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

African (AFR)

AF:

0.0637

AC:

2130

AN:

33456

American (AMR)

AF:

0.0112

AC:

503

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0408

AC:

1066

AN:

26120

East Asian (EAS)

AF:

0.0251

AC:

995

AN:

39688

South Asian (SAS)

AF:

0.112

AC:

9687

AN:

86234

European-Finnish (FIN)

AF:

0.0162

AC:

866

AN:

53404

Middle Eastern (MID)

AF:

0.0385

AC:

222

AN:

5760

European-Non Finnish (NFE)

AF:

0.0178

AC:

19818

AN:

1111382

Other (OTH)

AF:

0.0284

AC:

1714

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1711

3421

5132

6842

8553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

862

1724

2586

3448

4310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0325

AC:

4941

AN:

152244

Hom.:

137

Cov.:

AF XY:

0.0336

AC XY:

2497

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0605

AC:

2511

AN:

41530

American (AMR)

AF:

0.0165

AC:

253

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

154

AN:

3472

East Asian (EAS)

AF:

0.0247

AC:

128

AN:

5178

South Asian (SAS)

AF:

0.104

AC:

501

AN:

4812

European-Finnish (FIN)

AF:

0.0157

AC:

166

AN:

10604

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1157

AN:

68028

Other (OTH)

AF:

0.0289

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

231

462

692

923

1154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0218

Hom.:

Bravo

AF:

0.0322

Asia WGS

AF:

0.0580

AC:

200

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Leber congenital amaurosis 2 (1)

not specified (1)

Retinitis pigmentosa 87 with choroidal involvement (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.4

(source)

DANN

Benign

0.79

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over