12-88131237-A-T

Variant names:

• chr12-88131237-A-T
• rs113132803
• NM_025114.4:c.442-19T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025114.4(CEP290):​c.442-19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,457,462 control chromosomes in the GnomAD database, including 1,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (313 hom., cov: 31)
  • Exomes 𝑓: 0.032 (900 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.31
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-88131237-A-T is Benign according to our data. Variant chr12-88131237-A-T is described in ClinVar as Benign. ClinVar VariationId is 126259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.442-19T>A		intron_variant	Intron 6 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.442-19T>A		intron_variant	Intron 6 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7743 AN: 150430 Hom.: 310 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0386

Gnomad ASJ AF: 0.0574

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0344 AC: 2956 AN: 86040 AF XY: 0.0319

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.0211

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0371

GnomAD4 exome AF: 0.0320 AC: 41876 AN: 1306916 Hom.: 900 Cov.: 23 AF XY: 0.0317 AC XY: 20445 AN XY: 644236

African (AFR) AF: 0.113 AC: 2926 AN: 25904

American (AMR) AF: 0.0292 AC: 530 AN: 18130

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 1291 AN: 21882

East Asian (EAS) AF: 0.0449 AC: 1451 AN: 32288

South Asian (SAS) AF: 0.0173 AC: 1130 AN: 65340

European-Finnish (FIN) AF: 0.0254 AC: 1214 AN: 47828

Middle Eastern (MID) AF: 0.0298 AC: 133 AN: 4460

European-Non Finnish (NFE) AF: 0.0302 AC: 31276 AN: 1037076

Other (OTH) AF: 0.0356 AC: 1925 AN: 54008

GnomAD4 genome AF: 0.0515 AC: 7756 AN: 150546 Hom.: 313 Cov.: 31 AF XY: 0.0515 AC XY: 3779 AN XY: 73448

African (AFR) AF: 0.108 AC: 4457 AN: 41128

American (AMR) AF: 0.0386 AC: 577 AN: 14954

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 199 AN: 3464

East Asian (EAS) AF: 0.0294 AC: 149 AN: 5076

South Asian (SAS) AF: 0.0195 AC: 92 AN: 4724

European-Finnish (FIN) AF: 0.0273 AC: 277 AN: 10156

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0276 AC: 1868 AN: 67764

Other (OTH) AF: 0.0511 AC: 106 AN: 2076

Alfa AF: 0.0443 Hom.: 64

Bravo AF: 0.0540

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Sep 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.38
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113132803; hg19: chr12-88525014;