rs61941020

Positions:

• chr12-88079219-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025114.4(CEP290):​c.5237G>A​(p.Arg1746Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,577,480 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0099 (155 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21
• Conservation: PhyloP100: 2.76

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040839016).
• BP6: Variant 12-88079219-C-T is Benign according to our data. Variant chr12-88079219-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126262.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=8}. Variant chr12-88079219-C-T is described in Lovd as [Benign]. Variant chr12-88079219-C-T is described in Lovd as [Likely_benign]. Variant chr12-88079219-C-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00712 (1072/150466) while in subpopulation SAS AF= 0.043 (204/4748). AF 95% confidence interval is 0.0381. There are 7 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.5237G>A	p.Arg1746Gln	missense_variant	39/54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.5237G>A	p.Arg1746Gln	missense_variant	39/54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1075 AN: 150352 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00983

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00838

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00797

Gnomad OTH AF: 0.00920

GnomAD3 exomes AF: 0.0106 AC: 2316 AN: 217592 Hom.: 36 AF XY: 0.0123 AC XY: 1461 AN XY: 118348

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00723

Gnomad SAS exome AF: 0.0437

Gnomad FIN exome AF: 0.00262

Gnomad NFE exome AF: 0.00812

Gnomad OTH exome AF: 0.00862

GnomAD4 exome AF: 0.00992 AC: 14149 AN: 1427014 Hom.: 155 Cov.: 31 AF XY: 0.0109 AC XY: 7718 AN XY: 708210

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00523

Gnomad4 ASJ exome AF: 0.00654

Gnomad4 EAS exome AF: 0.00601

Gnomad4 SAS exome AF: 0.0403

Gnomad4 FIN exome AF: 0.00290

Gnomad4 NFE exome AF: 0.00855

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00712 AC: 1072 AN: 150466 Hom.: 7 Cov.: 31 AF XY: 0.00745 AC XY: 546 AN XY: 73332

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00982

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00840

Gnomad4 SAS AF: 0.0430

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00797

Gnomad4 OTH AF: 0.00910

Alfa AF: 0.00866 Hom.: 6

Bravo AF: 0.00648

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00195 AC: 7

ESP6500EA AF: 0.00971 AC: 79

ExAC AF: 0.0117 AC: 1412

Asia WGS AF: 0.0330 AC: 118 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2015	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2018	This variant is associated with the following publications: (PMID: 31734136, 30478281, 27491411) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CEP290: BP4, BS1, BS2 -

Retinal dystrophy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2013	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

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 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 15, 2019

- -

Leber congenital amaurosis 10 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Likely 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 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 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	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0055
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.11	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.47	.;.;P
Vest4		0.078
MPC		0.059
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.054
gMVP		0.14

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

Other links and lift over

dbSNP: rs61941020; hg19: chr12-88472996;