rs189556433

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_025114.4(CEP290):c.7186G>T(p.Asp2396Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,551,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2396H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 0.607

Publications

3 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 links:

RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

RLIG1 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=0.0067878366).

BP6

Variant 12-88050377-C-A is Benign according to our data. Variant chr12-88050377-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310589.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000762 (116/152252) while in subpopulation EAS AF = 0.0155 (80/5170). AF 95% confidence interval is 0.0127. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.7186G>T	p.Asp2396Tyr	missense	Exon 53 of 54	NP_079390.3	O15078
	RLIG1	NM_001009894.3	MANE Select	c.*1955C>A		downstream_gene	N/A	NP_001009894.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEP290	ENST00000552810.6	TSL:1 MANE Select	c.7186G>T	p.Asp2396Tyr	missense	Exon 53 of 54	ENSP00000448012.1	O15078
CEP290	ENST00000547691.8	TSL:1	c.4153G>T	p.Asp1385Tyr	missense	Exon 27 of 28	ENSP00000446905.3	A0A5K1VW81
CEP290	ENST00000675476.1		c.8047G>T	p.Asp2683Tyr	missense	Exon 55 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes

AF:

0.000776

AC:

118

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0156

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00118

AC:

276

AN:

234544

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.000340

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.000535

GnomAD4 exome

AF:

0.000342

AC:

479

AN:

1399730

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

254

AN XY:

698514

show subpopulations

African (AFR)

AF:

0.000284

AC:

AN:

31654

American (AMR)

AF:

0.00

AC:

AN:

41850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25604

East Asian (EAS)

AF:

0.00716

AC:

277

AN:

38684

South Asian (SAS)

AF:

0.00124

AC:

100

AN:

80850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52238

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5306

European-Non Finnish (NFE)

AF:

0.00000751

AC:

AN:

1065436

Other (OTH)

AF:

0.00145

AC:

AN:

58108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000762

AC:

116

AN:

152252

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0155

AC:

AN:

5170

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68000

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000261

Hom.:

Bravo

AF:

0.000688

ESP6500AA

AF:

0.000276

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00113

AC:

136

Asia WGS

AF:

0.0120

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Bardet-Biedl syndrome 14 (1)

Joubert syndrome 5 (1)

Leber congenital amaurosis (1)

Leber congenital amaurosis 10 (1)

Meckel syndrome, type 4 (1)

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

not specified (1)

Retinal dystrophy (1)

Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.0068

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.1

PhyloP100

0.61

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

REVEL

Benign

0.15

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.010

Polyphen

0.91

Vest4

0.54

MVP

0.76

MPC

0.32

ClinPred

0.048

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.073

gMVP

0.42

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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