rs117122459

Variant names:

• chr12-88087855-T-C
• rs117122459
• NM_025114.4:c.4119A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-88087855-T-C
• chr12-88087855-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_025114.4(CEP290):​c.4119A>G​(p.Lys1373Lys) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.685

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: 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: Synonymous conserved (PhyloP=0.685 with no splicing effect.
• BS1: 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. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 80 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.4119A>G	p.Lys1373Lys	synonymous_variant	Exon 32 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.4119A>G	p.Lys1373Lys	synonymous_variant	Exon 32 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3710 AN: 152126 Hom.: 80 Cov.: 32

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

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

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 AF: 0.0243 AC: 3700 AN: 152244 Hom.: 80 Cov.: 32 AF XY: 0.0267 AC XY: 1991 AN XY: 74452

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:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Kidney disorder Benign:1

Sep 07, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Senior-Loken syndrome 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Leber congenital amaurosis Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 14 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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

Other links and lift over

dbSNP: rs117122459; hg19: chr12-88481632;