rs188164241

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_025114.4(CEP290):c.1079G>A(p.Arg360Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00489 in 1,312,108 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R360R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 18 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:11

Conservation

PhyloP100: 4.75

Publications

10 publications found

Variant links:

Genes affected

CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

CEP290 Gene-Disease associations (from GenCC):

CEP290-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Bardet-Biedl syndrome 14
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Leber congenital amaurosis 10
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP290 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007601261).

BP6

Variant 12-88125356-C-T is Benign according to our data. Variant chr12-88125356-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166838.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025114.4. 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
	CEP290	NM_025114.4	MANE Select	c.1079G>A	p.Arg360Gln	missense	Exon 13 of 54	NP_079390.3	O15078

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEP290	ENST00000552810.6	TSL:1 MANE Select	c.1079G>A	p.Arg360Gln	missense	Exon 13 of 54	ENSP00000448012.1	O15078
CEP290	ENST00000604024.5	TSL:1	c.245G>A	p.Arg82Gln	missense	Exon 4 of 20	ENSP00000473863.1	S4R322
CEP290	ENST00000547926.7	TSL:1	n.1079G>A		non_coding_transcript_exon	Exon 13 of 21	ENSP00000448573.3	F8VS29

Frequencies

GnomAD3 genomes

AF:

0.00389

AC:

590

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000822

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00243

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00539

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00524

AC:

423

AN:

80670

AF XY:

0.00462

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.000183

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.00481

Gnomad OTH exome

AF:

0.00275

GnomAD4 exome

AF:

0.00502

AC:

5822

AN:

1160210

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

2823

AN XY:

567962

show subpopulations

African (AFR)

AF:

0.000845

AC:

AN:

23664

American (AMR)

AF:

0.00151

AC:

AN:

16562

Ashkenazi Jewish (ASJ)

AF:

0.000302

AC:

AN:

19840

East Asian (EAS)

AF:

0.00

AC:

AN:

27962

South Asian (SAS)

AF:

0.000223

AC:

AN:

40424

European-Finnish (FIN)

AF:

0.0140

AC:

605

AN:

43082

Middle Eastern (MID)

AF:

0.000825

AC:

AN:

4848

European-Non Finnish (NFE)

AF:

0.00529

AC:

4953

AN:

936232

Other (OTH)

AF:

0.00420

AC:

200

AN:

47596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

216

432

649

865

1081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00388

AC:

590

AN:

151898

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

297

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.000820

AC:

AN:

41488

American (AMR)

AF:

0.00243

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0139

AC:

147

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00540

AC:

366

AN:

67836

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00378

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000867

AC:

ESP6500EA

AF:

0.00463

AC:

ExAC

AF:

0.00129

AC:

116

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Meckel syndrome, type 4 (3)

not provided (3)

Bardet-Biedl syndrome 14 (2)

Joubert syndrome 5 (2)

Senior-Loken syndrome 6 (2)

Atypical hemolytic-uremic syndrome (1)

Joubert syndrome 1 (1)

Leber congenital amaurosis (1)

Leber congenital amaurosis 10 (1)

Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.070

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

PhyloP100

4.8

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.44

MVP

0.76

MPC

0.31

ClinPred

0.037

GERP RS

5.4

Varity_R

0.32

gMVP

0.50

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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