12-88139153-C-T

Variant names:

• chr12-88139153-C-T
• rs386834153
• NM_025114.4:c.289G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025114.4(CEP290):​c.289G>A​(p.Glu97Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000964 in 1,036,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E97D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.32
• 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]

CEP290 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.289G>A	p.Glu97Lys	missense_variant	Exon 5 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.289G>A	p.Glu97Lys	missense_variant	Exon 5 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.64e-7 AC: 1 AN: 1036934 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 522590

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21716

American (AMR) AF: 0.00 AC: 0 AN: 24504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19266

East Asian (EAS) AF: 0.00 AC: 0 AN: 30350

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 793728

Other (OTH) AF: 0.00 AC: 0 AN: 43748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	.;T;.;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	.;M;.;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0080	D;D;T;D;.
Sift4G	Benign	0.13	T;T;T;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.68
MutPred		0.31		Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);.;
MVP		0.95
MPC		0.36
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.42
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs386834153; hg19: chr12-88532930;