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rs117122459

chr12-88087855-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_025114.4(CEP290):c.4119A>G(p.Lys1373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,268,110 control chromosomes in the GnomAD database, including 693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 80 hom., cov: 32)
Exomes 𝑓: 0.031 ( 613 hom. )

Consequence

CEP290
NM_025114.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.685
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-88087855-T-C is Benign according to our data. Variant chr12-88087855-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 126258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88087855-T-C is described in Lovd as [Benign]. Variant chr12-88087855-T-C is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.685 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0243 (3700/152244) while in subpopulation SAS AF= 0.0446 (215/4824). AF 95% confidence interval is 0.0397. There are 80 homozygotes in gnomad4. There are 1991 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 80 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CEP290NM_025114.4 linkuse as main transcriptc.4119A>G p.Lys1373= synonymous_variant 32/54 ENST00000552810.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CEP290ENST00000552810.6 linkuse as main transcriptc.4119A>G p.Lys1373= synonymous_variant 32/541 NM_025114.4 P4

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0244
AC:
3710
AN:
152126
Hom.:
80
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00596
Gnomad AMI
AF:
0.112
Gnomad AMR
AF:
0.0268
Gnomad ASJ
AF:
0.0130
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.0458
Gnomad FIN
AF:
0.0694
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.0278
Gnomad OTH
AF:
0.0244
GnomAD3 exomes
AF:
0.0364
AC:
2068
AN:
56816
Hom.:
63
AF XY:
0.0375
AC XY:
1152
AN XY:
30738
show subpopulations
Gnomad AFR exome
AF:
0.00223
Gnomad AMR exome
AF:
0.0231
Gnomad ASJ exome
AF:
0.0124
Gnomad EAS exome
AF:
0.00117
Gnomad SAS exome
AF:
0.0472
Gnomad FIN exome
AF:
0.0638
Gnomad NFE exome
AF:
0.0283
Gnomad OTH exome
AF:
0.0161
GnomAD4 exome
AF:
0.0312
AC:
34769
AN:
1115866
Hom.:
613
Cov.:
19
AF XY:
0.0309
AC XY:
16659
AN XY:
539976
show subpopulations
Gnomad4 AFR exome
AF:
0.00473
Gnomad4 AMR exome
AF:
0.0239
Gnomad4 ASJ exome
AF:
0.0115
Gnomad4 EAS exome
AF:
0.000368
Gnomad4 SAS exome
AF:
0.0440
Gnomad4 FIN exome
AF:
0.0579
Gnomad4 NFE exome
AF:
0.0320
Gnomad4 OTH exome
AF:
0.0263
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0243
AC:
3700
AN:
152244
Hom.:
80
Cov.:
32
AF XY:
0.0267
AC XY:
1991
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.00594
Gnomad4 AMR
AF:
0.0267
Gnomad4 ASJ
AF:
0.0130
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.0446
Gnomad4 FIN
AF:
0.0694
Gnomad4 NFE
AF:
0.0277
Gnomad4 OTH
AF:
0.0241
Alfa
AF:
0.0241
Hom.:
23
Bravo
AF:
0.0206
Asia WGS
AF:
0.0300
AC:
104
AN:
3472

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 09, 2023- -
Kidney disorder Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 07, 2022- -
Senior-Loken syndrome 6 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Leber congenital amaurosis 10 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Leber congenital amaurosis Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Bardet-Biedl syndrome 14 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Meckel syndrome, type 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Joubert syndrome 5 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
Cadd
Benign
9.0
Dann
Benign
0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs117122459; hg19: chr12-88481632; API