rs569673313

chr12-88049228-ACT-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_025114.4(CEP290):c.7394_7395del(p.Glu2465ValfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,604,266 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:2
• Conservation: PhyloP100: 2.74

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]

RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2478 codons.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.7394_7395del	p.Glu2465ValfsTer2	frameshift_variant	54/54	ENST00000552810.6
RLIG1	NM_001009894.3	c.*809_*810del		3_prime_UTR_variant	7/7	ENST00000356891.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.7394_7395del	p.Glu2465ValfsTer2	frameshift_variant	54/54	1	NM_025114.4	P4
RLIG1	ENST00000356891.4	c.*809_*810del		3_prime_UTR_variant	7/7	1	NM_001009894.3	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000598 AC: 144 AN: 241004 Hom.: 2 AF XY: 0.000826 AC XY: 108 AN XY: 130746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000900

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00419

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000323 AC: 469 AN: 1452268 Hom.: 5 AF XY: 0.000452 AC XY: 326 AN XY: 721668

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000631

Gnomad4 OTH exome AF: 0.000484

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CEP290 p.Glu2465Valfs*2 variant was not identified in the literature but was identified in dbSNP (ID: rs569673313) and ClinVar (classified as benign by Invitae; as likely pathogenic by CeGaT Praxis; and as uncertain significance by GeneDx and Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 144 of 241004 chromosomes (2 homozygous) at a frequency of 0.0005975 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 119 of 28430 chromosomes (freq: 0.004186), European (non-Finnish) in 21 of 108954 chromosomes (freq: 0.000193), Ashkenazi Jewish in 1 of 9878 chromosomes (freq: 0.000101) and Latino in 3 of 33318 chromosomes (freq: 0.00009), but was not observed in the African, East Asian, European (Finnish), or Other populations. The c.7394_7395del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2465 and leads to a premature stop codon at position 2. This variant occurs in the last exon of the CEP290 gene, therefore it is not expected to result in loss of function. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2016	A variant of uncertain significance has been identified in the CEP290 gene. The c.7394_7395delAG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.7394_7395delAG variant is observed in 72/16,502 (0.4%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.7394_7395delAG variant causes a frameshift starting with codon Glutamic acid 2465, changes this amino acid to a Valine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Glu2465ValfsX2. This variant is predicted to cause loss of normal protein function through protein truncation as the last 15 amino acids of the CEP290 protein and lost and replaced with 1 incorrect amino acid. However, this deletion occurs in a region that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	Variant summary: CEP290 c.7394_7395delAG (p.Glu2465ValfsX2) results in a premature termination codon. The variant is not predicted to undergo NMD. The variant allele was found at a frequency of 0.0006 in 241004 control chromosomes, predominantly at a frequency of 0.0042 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in CEP290 causing Meckel Syndrome Type 4 phenotype (0.0011), suggesting that the variant may be a benign polymorphism found primarily in populations of South Asian origin. c.7394_7395delAG has been reported in the literature in individuals with Joubert Syndrome 5 and nonsyndromic retinal dystrophy with second variants of unknown signficance (Iyer_2022, Testa_2021). Additional patients with retinitis pigmentosa and Joubert Syndrome have been reported in the heterozygous state (Bohorquez_2021, Devi_2020) These reports do not provide unequivocal conclusions about association of the variant with Meckel Syndrome Type 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 372319). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Bardet-Biedl syndrome 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Joubert syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs569673313; hg19: chr12-88443005;