rs45468703

Variant names:

• chr12-88139109-T-C
• rs45468703
• NM_025114.4:c.297+36A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025114.4(CEP290):​c.297+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,072,728 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (78 hom., cov: 32)
  • Exomes 𝑓: 0.019 (262 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.823
• 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=-0.61).
• BP6: Variant 12-88139109-T-C is Benign according to our data. Variant chr12-88139109-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0281 (4277/152250) while in subpopulation AFR AF = 0.0501 (2081/41552). AF 95% confidence interval is 0.0483. There are 78 homozygotes in GnomAd4. There are 2090 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.297+36A>G		intron_variant	Intron 5 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.297+36A>G		intron_variant	Intron 5 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4266 AN: 152132 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0169 AC: 2810 AN: 166694 AF XY: 0.0157

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0192 AC: 17696 AN: 920478 Hom.: 262 Cov.: 12 AF XY: 0.0187 AC XY: 8848 AN XY: 473754

African (AFR) AF: 0.0475 AC: 1006 AN: 21198

American (AMR) AF: 0.0142 AC: 465 AN: 32702

Ashkenazi Jewish (ASJ) AF: 0.00140 AC: 29 AN: 20716

East Asian (EAS) AF: 0.0388 AC: 1285 AN: 33120

South Asian (SAS) AF: 0.00358 AC: 236 AN: 65888

European-Finnish (FIN) AF: 0.0231 AC: 1101 AN: 47734

Middle Eastern (MID) AF: 0.00761 AC: 35 AN: 4600

European-Non Finnish (NFE) AF: 0.0195 AC: 12736 AN: 653422

Other (OTH) AF: 0.0195 AC: 803 AN: 41098

GnomAD4 genome AF: 0.0281 AC: 4277 AN: 152250 Hom.: 78 Cov.: 32 AF XY: 0.0281 AC XY: 2090 AN XY: 74452

African (AFR) AF: 0.0501 AC: 2081 AN: 41552

American (AMR) AF: 0.0260 AC: 398 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.0255 AC: 270 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0190 AC: 1293 AN: 68008

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0192 Hom.: 14

Bravo AF: 0.0281

Asia WGS AF: 0.0150 AC: 52 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.3
DANN	Benign	0.91
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45468703; hg19: chr12-88532886;