12-88049228-ACT-A

Position:

chr12-88049228-ACT-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:3

Conservation

PhyloP100: 2.74

Variant links:

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 links:

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]

RLIG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.7394_7395del	p.Glu2465ValfsTer2	frameshift_variant	54/54	ENST00000552810.6
RLIG1	NM_001009894.3 linkuse as main transcript	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 linkuse as main transcript	c.7394_7395del	p.Glu2465ValfsTer2	frameshift_variant	54/54	1	NM_025114.4	P4
RLIG1	ENST00000356891.4 linkuse as main transcript	c.809_810del		3_prime_UTR_variant	7/7	1	NM_001009894.3	P1	Q8N999-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151880

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000826

AC XY:

108

AN XY:

130746

show subpopulations

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.:

AF XY:

0.000452

AC XY:

326

AN XY:

721668

show subpopulations

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:

AN:

151998

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74312

show subpopulations

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.:

Bravo

AF:

0.0000491

Asia WGS

AF:

0.000580

AC:

AN:

3462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
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. -

not specified

Uncertain:1Benign:1

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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2024	Variant summary: CEP290 c.7394_7395delAG (p.Glu2465ValfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00031 in 1604266 control chromosomes, predominantly at a frequency of 0.0042 within the South Asian subpopulation in the gnomAD database, including 5 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). c.7394_7395delAG has been reported in the literature in individuals with molecular diagnosis of Joubert syndrome or clinical diagnosis of nonsyndromic retinal dystrophy (Iyer_2022, Testa_2021). Additional patients with retinitis pigmentosa or clinical features of Joubert Syndrome have been reported in the heterozygous state (Bohorquez_2021, Devi_2020), an insufficient genotype. 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. The following publications have been ascertained in the context of this evaluation (PMID: 34327195, 32139166, 35123515, 22848652, 34196655). ClinVar contains an entry for this variant (Variation ID: 372319). Based on the evidence outlined above, the variant was classified as benign. -

CEP290-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The CEP290 c.7394_7395delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu2465Valfs*2). This deletion is near the C-terminus of the CEP290 protein and is predicted to result in a protein that is 12 amino acids shorter than the reference protein. This variant has been reported as a variant of uncertain significance in a large cohort study of patients with obesity (Savas et al. 2019. PubMed ID: 31216558). This variant is reported in 0.42% of alleles in individuals of South Asian descent in gnomAD, including two homozygotes. This population data provides evidence against pathogenicity. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over