rs115837670

Variant names:

• chr12-88109218-A-C
• rs115837670
• NM_025114.4:c.2368-37T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-88109218-A-C
• chr12-88109218-A-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.2368-37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 677,942 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (140 hom., cov: 32)
  • Exomes 𝑓: 0.021 (180 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0850
• Publications: 2 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=-0.86).
• BP6: Variant 12-88109218-A-C is Benign according to our data. Variant chr12-88109218-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.2368-37T>G		intron_variant	Intron 22 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.2368-37T>G		intron_variant	Intron 22 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5276 AN: 152050 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0184 AC: 1379 AN: 75044 AF XY: 0.0165

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.00165

Gnomad EAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0209 AC: 11006 AN: 525774 Hom.: 180 Cov.: 7 AF XY: 0.0197 AC XY: 5545 AN XY: 282142

African (AFR) AF: 0.0730 AC: 743 AN: 10182

American (AMR) AF: 0.0198 AC: 219 AN: 11076

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 38 AN: 16358

East Asian (EAS) AF: 0.0466 AC: 1208 AN: 25908

South Asian (SAS) AF: 0.00368 AC: 164 AN: 44584

European-Finnish (FIN) AF: 0.0234 AC: 1090 AN: 46538

Middle Eastern (MID) AF: 0.00980 AC: 25 AN: 2550

European-Non Finnish (NFE) AF: 0.0202 AC: 6897 AN: 340760

Other (OTH) AF: 0.0224 AC: 622 AN: 27818

GnomAD4 genome AF: 0.0348 AC: 5289 AN: 152168 Hom.: 140 Cov.: 32 AF XY: 0.0347 AC XY: 2583 AN XY: 74400

African (AFR) AF: 0.0730 AC: 3030 AN: 41530

American (AMR) AF: 0.0279 AC: 426 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3464

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5172

South Asian (SAS) AF: 0.00312 AC: 15 AN: 4814

European-Finnish (FIN) AF: 0.0258 AC: 274 AN: 10612

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0193 AC: 1313 AN: 67976

Other (OTH) AF: 0.0359 AC: 76 AN: 2116

Alfa AF: 0.0239 Hom.: 21

Bravo AF: 0.0352

Asia WGS AF: 0.0160 AC: 54 AN: 3462

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: Likely 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: 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	-0.86
CADD	Benign	1.8
DANN	Benign	0.35
PhyloP100		0.085
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: rs115837670; hg19: chr12-88502995;