12-88055666-A-T

Position:

• chr12-88055666-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025114.4(CEP290):​c.6870T>A​(p.Asn2290Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320

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 (HGNC:):

ACMG classification

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=0.11130586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.6870T>A	p.Asn2290Lys	missense_variant	50/54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.6870T>A	p.Asn2290Lys	missense_variant	50/54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	.;.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.074	T;D;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.16	.;.;B
Vest4		0.18
MutPred		0.23		.;.;Loss of ubiquitination at K2288 (P = 0.0219);
MVP		0.62
MPC		0.081
ClinPred		0.59	D
GERP RS		-0.30
Varity_R		0.050
gMVP		0.35

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: rs572443869; hg19: chr12-88449443;