NM_025114.4:c.7035-38C>G

Variant names:

• chr12-88053784-G-C
• rs45477492
• NM_025114.4:c.7035-38C>G

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.7035-38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,055,992 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (151 hom., cov: 32)
  • Exomes 𝑓: 0.021 (298 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.172
• Publications: 1 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=-0.84).
• BP6: Variant 12-88053784-G-C is Benign according to our data. Variant chr12-88053784-G-C is described in ClinVar as Benign. ClinVar VariationId is 126267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.7035-38C>G		intron_variant	Intron 51 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.7035-38C>G		intron_variant	Intron 51 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5413 AN: 152092 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0197 AC: 2542 AN: 128932 AF XY: 0.0181

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0208 AC: 18813 AN: 903782 Hom.: 298 Cov.: 12 AF XY: 0.0200 AC XY: 9202 AN XY: 460596

African (AFR) AF: 0.0796 AC: 1656 AN: 20792

American (AMR) AF: 0.0196 AC: 510 AN: 26018

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 26 AN: 21270

East Asian (EAS) AF: 0.0401 AC: 1330 AN: 33166

South Asian (SAS) AF: 0.00363 AC: 218 AN: 60122

European-Finnish (FIN) AF: 0.0235 AC: 1048 AN: 44658

Middle Eastern (MID) AF: 0.00677 AC: 25 AN: 3694

European-Non Finnish (NFE) AF: 0.0201 AC: 13136 AN: 652372

Other (OTH) AF: 0.0207 AC: 864 AN: 41690

GnomAD4 genome AF: 0.0357 AC: 5429 AN: 152210 Hom.: 151 Cov.: 32 AF XY: 0.0354 AC XY: 2635 AN XY: 74418

African (AFR) AF: 0.0772 AC: 3209 AN: 41542

American (AMR) AF: 0.0274 AC: 419 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5186

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0259 AC: 274 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0190 AC: 1293 AN: 68000

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.0235 Hom.: 15

Bravo AF: 0.0360

Asia WGS AF: 0.0180 AC: 63 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.91
DANN	Benign	0.57
PhyloP100		-0.17
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: rs45477492; hg19: chr12-88447561;