12-88089351-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025114.4(CEP290):c.3710G>A(p.Arg1237His) variant causes a missense change. The variant allele was found at a frequency of 0.00905 in 1,613,838 control chromosomes in the GnomAD database, including 1,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1237C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.050 ( 637 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 561 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.92

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016953051).

BP6

Variant 12-88089351-C-T is Benign according to our data. Variant chr12-88089351-C-T is described in ClinVar as Benign. ClinVar VariationId is 126257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

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.3710G>A	p.Arg1237His	missense	Exon 31 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.3710G>A	p.Arg1237His	missense	Exon 31 of 54	ENSP00000448012.1	O15078
CEP290	ENST00000547691.8	TSL:1	c.992G>A	p.Arg331His	missense	Exon 7 of 28	ENSP00000446905.3	A0A5K1VW81
CEP290	ENST00000675476.1		c.4571G>A	p.Arg1524His	missense	Exon 33 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes

AF:

0.0495

AC:

7531

AN:

152036

Hom.:

636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0120

AC:

2978

AN:

249060

AF XY:

0.00889

show subpopulations

Gnomad AFR exome

AF:

0.173

Gnomad AMR exome

AF:

0.00669

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00483

AC:

7060

AN:

1461684

Hom.:

561

Cov.:

AF XY:

0.00413

AC XY:

3001

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.176

AC:

5888

AN:

33472

American (AMR)

AF:

0.00832

AC:

372

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000417

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000102

AC:

113

AN:

1111866

Other (OTH)

AF:

0.0103

AC:

621

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

345

690

1035

1380

1725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.0496

AC:

7543

AN:

152154

Hom.:

637

Cov.:

AF XY:

0.0477

AC XY:

3550

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.172

AC:

7142

AN:

41470

American (AMR)

AF:

0.0205

AC:

314

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68020

Other (OTH)

AF:

0.0289

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

310

620

929

1239

1549

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:

0.0160

Hom.:

432

Bravo

AF:

0.0560

ESP6500AA

AF:

0.168

AC:

632

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0146

AC:

1766

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

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 provided (1)

Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

5.9

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

REVEL

Benign

0.22

Sift

Benign

0.074

Sift4G

Benign

0.069

Polyphen

0.76

Vest4

0.11

MPC

0.38

ClinPred

0.034

GERP RS

5.6

Varity_R

0.15

gMVP

0.32

Mutation Taster

=61/39

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