12-88114481-T-C

Position:

• chr12-88114481-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000552810.6(CEP290):​c.1991A>G​(p.Asp664Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,548,028 control chromosomes in the GnomAD database, including 1,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D664D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (161 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1363 hom.)
• Consequence: CEP290 ENST00000552810.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 5.83

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 Benign. Variant got -18 ACMG points.

• PM1: In a coiled_coil_region (size 66) in uniprot entity CE290_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000552810.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.001729846).
• BP6: Variant 12-88114481-T-C is Benign according to our data. Variant chr12-88114481-T-C is described in ClinVar as [Benign]. Clinvar id is 100592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88114481-T-C is described in Lovd as [Likely_benign]. Variant chr12-88114481-T-C is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.1991A>G	p.Asp664Gly	missense_variant	20/54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.1991A>G	p.Asp664Gly	missense_variant	20/54	1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3462 AN: 152128 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.00388

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0335 AC: 5244 AN: 156596 Hom.: 231 AF XY: 0.0294 AC XY: 2414 AN XY: 82146

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.0919

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.00790

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0219 AC: 30498 AN: 1395780 Hom.: 1363 Cov.: 29 AF XY: 0.0211 AC XY: 14520 AN XY: 688316

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.0968

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.00716

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0228 AC: 3467 AN: 152248 Hom.: 161 Cov.: 32 AF XY: 0.0244 AC XY: 1816 AN XY: 74438

Gnomad4 AFR AF: 0.00387

Gnomad4 AMR AF: 0.0841

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0178 Hom.: 99

Bravo AF: 0.0266

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00316 AC: 11

ESP6500EA AF: 0.0122 AC: 94

ExAC AF: 0.0111 AC: 748

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic 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 provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Retinal dystrophy Benign:2

Benign, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Benign, no assertion criteria provided	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2012	- -

Joubert syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Joubert syndrome 5, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS4 => Lack of segregation in affected members of a family (PMID:17564967). -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2019

- -

Senior-Loken syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Bardet-Biedl syndrome 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Meckel syndrome, type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	.;M;.;.
MutationTaster	Benign	0.085	P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;N;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.011	D;D;.;.
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.20	.;B;.;.
Vest4		0.15
MPC		0.31
ClinPred		0.018	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.21

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: rs79705698; hg19: chr12-88508258; COSMIC: COSV58351871;