rs373913704

Variant names:

• chr12-88139519-C-T
• rs373913704
• NM_025114.4:c.226G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 6.23

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.226G>A	p.Ala76Thr	missense_variant	Exon 4 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.226G>A	p.Ala76Thr	missense_variant	Exon 4 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.000560 AC: 85 AN: 151892 Hom.: 0 Cov.: 33

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

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

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

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:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Sep 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In 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) -

Jan 30, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CEP290: PM2, PP3 -

not specified Uncertain:2

Apr 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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. -

Nov 05, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA 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. -

Senior-Loken syndrome 6 Uncertain:1

Jun 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The 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

Jun 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jun 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jun 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jun 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Apr 19, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

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