rs2033224468

Variant names:

• chr12-88049194-G-A
• rs2033224468
• NM_025114.4:c.7430C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-88049194-G-A
• chr12-88049194-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025114.4(CEP290):​c.7430C>T​(p.Pro2477Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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: 3.74

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34523475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.7430C>T	p.Pro2477Leu	missense_variant	Exon 54 of 54	ENST00000552810.6	NP_079390.3
RLIG1	NM_001009894.3	c.*772G>A		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.7430C>T	p.Pro2477Leu	missense_variant	Exon 54 of 54	1	NM_025114.4	ENSP00000448012.1
C12orf29	ENST00000356891.4	c.*772G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_001009894.3	ENSP00000349358.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	.;.;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.0040	.;.;B
Vest4		0.65
MutPred		0.32		.;.;Gain of catalytic residue at Y2479 (P = 0.0233);
MVP		0.76
MPC		0.35
ClinPred		0.65	D
GERP RS		5.3
Varity_R		0.10
gMVP		0.56

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: rs2033224468; hg19: chr12-88442971;