rs201982308

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025114.4(CEP290):c.3660G>T(p.Lys1220Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 1,612,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K1220K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.585

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1110214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.3660G>T	p.Lys1220Asn	missense_variant	31/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.3660G>T	p.Lys1220Asn	missense_variant	31/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000244

AC:

AN:

245532

Hom.:

AF XY:

0.000203

AC XY:

AN XY:

133100

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000234

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000433

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000462

AC:

675

AN:

1460550

Hom.:

Cov.:

AF XY:

0.000428

AC XY:

311

AN XY:

726390

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000587

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000223

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000265

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.000240

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.3660G>T (p.K1220N) alteration is located in exon 31 (coding exon 30) of the CEP290 gene. This alteration results from a G to T substitution at nucleotide position 3660, causing the lysine (K) at amino acid position 1220 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CEP290-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The CEP290 c.3660G>T variant is predicted to result in the amino acid substitution p.Lys1220Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Leber congenital amaurosis

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 21, 2020

- -

Bardet-Biedl syndrome 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Jan 01, 2022

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1220 of the CEP290 protein (p.Lys1220Asn). This variant is present in population databases (rs201982308, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 196713). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CEP290 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Uncertain

-0.15

MutationTaster

Benign

0.55

D;D;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.99

.;.;D

Vest4

0.18

MutPred

0.25

.;.;Loss of ubiquitination at K1220 (P = 0.0148);

MVP

0.79

MPC

0.060

ClinPred

0.19

GERP RS

4.6

Varity_R

0.47

gMVP

0.41

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