rs764963626

Positions:

• chr12-88107031-C-G
• chr12-88107031-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_025114.4(CEP290):​c.2551G>C​(p.Val851Leu) 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: 1.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest Interaction with IQCB1 (size 200) in uniprot entity CE290_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_025114.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03437382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.2551G>C	p.Val851Leu	missense_variant	24/54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.2551G>C	p.Val851Leu	missense_variant	24/54	1	NM_025114.4	ENSP00000448012	P4

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	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.73
DEOGEN2	Benign	0.097	.;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N;N;.
REVEL	Benign	0.043
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0070	.;B;.
Vest4		0.077
MutPred		0.18		.;Gain of loop (P = 0.1081);.;
MVP		0.17
MPC		0.052
ClinPred		0.070	T
GERP RS		0.19
Varity_R		0.040
gMVP		0.060

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: rs764963626; hg19: chr12-88500808;