rs373913704

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_025114.4(CEP290):​c.226G>A​(p.Ala76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000763 in 1,597,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00078 ( 1 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

2
10
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 6.23
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04635045).
BP6
Variant 12-88139519-C-T is Benign according to our data. Variant chr12-88139519-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166841.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}. Variant chr12-88139519-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CEP290NM_025114.4 linkuse as main transcriptc.226G>A p.Ala76Thr missense_variant 4/54 ENST00000552810.6 NP_079390.3 O15078Q05BJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkuse as main transcriptc.226G>A p.Ala76Thr missense_variant 4/541 NM_025114.4 ENSP00000448012.1 O15078

Frequencies

GnomAD3 genomes
AF:
0.000560
AC:
85
AN:
151892
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000525
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000667
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000912
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000629
AC:
150
AN:
238306
Hom.:
0
AF XY:
0.000641
AC XY:
83
AN XY:
129488
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000218
Gnomad ASJ exome
AF:
0.00256
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000178
Gnomad FIN exome
AF:
0.000235
Gnomad NFE exome
AF:
0.000932
Gnomad OTH exome
AF:
0.00105
GnomAD4 exome
AF:
0.000784
AC:
1133
AN:
1445078
Hom.:
1
Cov.:
30
AF XY:
0.000820
AC XY:
589
AN XY:
718542
show subpopulations
Gnomad4 AFR exome
AF:
0.000122
Gnomad4 AMR exome
AF:
0.000258
Gnomad4 ASJ exome
AF:
0.00195
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000219
Gnomad4 FIN exome
AF:
0.000247
Gnomad4 NFE exome
AF:
0.000903
Gnomad4 OTH exome
AF:
0.000638
GnomAD4 genome
AF:
0.000559
AC:
85
AN:
152010
Hom.:
0
Cov.:
33
AF XY:
0.000633
AC XY:
47
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.000524
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000667
Gnomad4 NFE
AF:
0.000912
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00110
Hom.:
1
Bravo
AF:
0.000495
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000276
AC:
1
ESP6500EA
AF:
0.000737
AC:
6
ExAC
AF:
0.000580
AC:
70

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024CEP290: PM2, PP3 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 23, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27323230, 25920555, 32036094, 33308271) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 30, 2014- -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 05, 2021DNA sequence analysis of the CEP290 gene demonstrated a sequence change, c.226G>A, in exon 4 that results in an amino acid change, p.Ala76Thr. This sequence change does not appear to have been previously described in patients with CEP290-related disorders and has been described in the gnomAD database with a low population frequency of 0.25% in Ashkenazi Jews subpopulation (dbSNP rs373913704). The p.Ala76Thr change affects a moderately conserved amino acid residue located in a domain of the CEP290 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala76Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala76Thr change remains unknown at this time. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 01, 2022Variant summary: CEP290 c.226G>A (p.Ala76Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 238306 control chromosomes, predominantly at a frequency of 0.00093 within the Non-Finnish European subpopulation in the gnomAD database, however in certain subpopulations e.g. in the Estonians, Bulgarians and Ashkenazi Jewish, the variant occurred with an even higher frequency, 0.0025-0.0029, which might suggest a benign role for the variant. The variant, c.226G>A, has been reported in the literature in heterozygous state in individuals affected with various disease phenotypes e.g. Joubert syndrome, Leber congenital amaurosis and cone-rod dystrophy, however in at least two of these cases other (potentially) pathogenic variants were also noted to co-occur (Kroes_2015, Skorczyk-Werner_2020, Rodriguez-Munoz_2020). These reports do not provide unequivocal conclusions about association of the variant with CEP290-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Senior-Loken syndrome 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 19, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
CEP290-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 30, 2024The CEP290 c.226G>A variant is predicted to result in the amino acid substitution p.Ala76Thr. This variant has been reported in the heterozygous state in two individuals with Joubert syndrome (Kroes et al. 2016. PubMed ID: 25920555, Supplementary Table S2). This variant has also been reported in the heterozygous state in an individual with Leber congenital amaurosis; however, this individual also harbored additional variants in another gene (Skorczyk-Werner et al. 2020. PubMed: 33308271, Table 2). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain. -
Leber congenital amaurosis 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 19, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Bardet-Biedl syndrome 14 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 19, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Meckel syndrome, type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 19, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Joubert syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 19, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.19
.;T;.;.;T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;D;D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Benign
0.046
T;T;T;T;T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.1
.;M;.;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.56
N;N;.;N;.
REVEL
Uncertain
0.29
Sift
Benign
0.040
D;D;.;T;.
Sift4G
Benign
0.41
T;T;T;T;D
Polyphen
1.0
.;D;.;.;.
Vest4
0.61
MVP
0.92
MPC
0.34
ClinPred
0.055
T
GERP RS
5.2
Varity_R
0.12
gMVP
0.25

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

LitVar

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

Other links and lift over

dbSNP: rs373913704; hg19: chr12-88533296; COSMIC: COSV99898512; COSMIC: COSV99898512; API