12-88121157-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025114.4(CEP290):c.1199C>G(p.Thr400Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T400I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06521022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.1199C>G	p.Thr400Ser	missense_variant	14/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.1199C>G	p.Thr400Ser	missense_variant	14/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246646 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459358 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	11
Dann	Benign	0.42
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.48	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.25	N;N;.;.
REVEL	Benign	0.073
Sift	Benign	0.57	T;T;.;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.10
MutPred		0.11		Gain of catalytic residue at G397 (P = 0.0519);Gain of catalytic residue at G397 (P = 0.0519);.;Gain of catalytic residue at G397 (P = 0.0519);
MVP		0.58
MPC		0.048
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.039
gMVP		0.047

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: rs773578133; hg19: chr12-88514934;