rs45468703

Positions:

• chr12-88139109-T-C

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -0.823

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 -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 [Likely_benign]. Clinvar id is 126254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88139109-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.297+36A>G		intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.297+36A>G		intron_variant		1	NM_025114.4	P4

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

GnomAD3 exomes AF: 0.0169 AC: 2810 AN: 166694 Hom.: 41 AF XY: 0.0157 AC XY: 1407 AN XY: 89850

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 SAS exome AF: 0.00329

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

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.00140

Gnomad4 EAS exome AF: 0.0388

Gnomad4 SAS exome AF: 0.00358

Gnomad4 FIN exome AF: 0.0231

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0195

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

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0255

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0193 Hom.: 6

Bravo AF: 0.0281

Asia WGS AF: 0.0150 AC: 52 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.3
DANN	Benign	0.91

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: rs45468703; hg19: chr12-88532886;