12-88049189-A-G

Variant names:

• chr12-88049189-A-G
• NM_025114.4:c.7435T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025114.4(CEP290):​c.7435T>C​(p.Tyr2479His) 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. 15/22 in silico tools predict 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. Y2479Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27008003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.7435T>C	p.Tyr2479His	missense_variant	Exon 54 of 54	ENST00000552810.6	NP_079390.3
RLIG1	NM_001009894.3	c.*767A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000356891.4	NP_001009894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.7435T>C	p.Tyr2479His	missense_variant	Exon 54 of 54	1	NM_025114.4	ENSP00000448012.1
RLIG1	ENST00000356891.4	c.*767A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_001009894.3	ENSP00000349358.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7435T>C (p.Y2479H) alteration is located in exon 54 (coding exon 53) of the CEP290 gene. This alteration results from a T to C substitution at nucleotide position 7435, causing the tyrosine (Y) at amino acid position 2479 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Leber congenital amaurosis Uncertain:1

Feb 27, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	.;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.90	.;.;L
PhyloP100		1.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.057
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.013	.;.;B
Vest4		0.52
MutPred		0.34		.;.;Gain of catalytic residue at N2475 (P = 0.0065);
MVP		0.41
MPC		0.37
ClinPred		0.59	D
GERP RS		4.1
Varity_R		0.19
gMVP		0.37
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

hg19: chr12-88442966;