NM_025114.4:c.5227-43G>A

Variant names:

• chr12-88079272-C-T
• rs2468245
• NM_025114.4:c.5227-43G>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.5227-43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 1,500,250 control chromosomes in the GnomAD database, including 618,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50393 hom., cov: 31)
  • Exomes 𝑓: 0.91 (567907 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.34
• Publications: 8 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

LOC124902977 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-88079272-C-T is Benign according to our data. Variant chr12-88079272-C-T is described in ClinVar as Benign. ClinVar VariationId is 126261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.5227-43G>A		intron_variant	Intron 38 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.5227-43G>A		intron_variant	Intron 38 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118679 AN: 151890 Hom.: 50392 Cov.: 31

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.897

Gnomad FIN AF: 0.962

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.820

GnomAD2 exomes AF: 0.896 AC: 157713 AN: 175992 AF XY: 0.902

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.923

Gnomad ASJ exome AF: 0.905

Gnomad EAS exome AF: 0.974

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.897

GnomAD4 exome AF: 0.914 AC: 1232581 AN: 1348242 Hom.: 567907 Cov.: 21 AF XY: 0.914 AC XY: 613175 AN XY: 670568

African (AFR) AF: 0.395 AC: 11014 AN: 27862

American (AMR) AF: 0.917 AC: 27910 AN: 30452

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 22131 AN: 24488

East Asian (EAS) AF: 0.952 AC: 33036 AN: 34702

South Asian (SAS) AF: 0.893 AC: 62031 AN: 69494

European-Finnish (FIN) AF: 0.961 AC: 48761 AN: 50764

Middle Eastern (MID) AF: 0.896 AC: 4928 AN: 5498

European-Non Finnish (NFE) AF: 0.927 AC: 972926 AN: 1048980

Other (OTH) AF: 0.890 AC: 49844 AN: 56002

GnomAD4 genome AF: 0.781 AC: 118694 AN: 152008 Hom.: 50393 Cov.: 31 AF XY: 0.787 AC XY: 58484 AN XY: 74326

African (AFR) AF: 0.410 AC: 16961 AN: 41400

American (AMR) AF: 0.866 AC: 13205 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3106 AN: 3472

East Asian (EAS) AF: 0.965 AC: 5006 AN: 5190

South Asian (SAS) AF: 0.897 AC: 4328 AN: 4824

European-Finnish (FIN) AF: 0.962 AC: 10173 AN: 10570

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.928 AC: 63064 AN: 67982

Other (OTH) AF: 0.822 AC: 1740 AN: 2116

Alfa AF: 0.847 Hom.: 10777

Bravo AF: 0.759

Asia WGS AF: 0.882 AC: 3052 AN: 3464

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

Jun 26, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0020
DANN	Benign	0.58
PhyloP100		-2.3
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: rs2468245; hg19: chr12-88473049;