12-88129717-C-T

Variant names:

• chr12-88129717-C-T
• rs45502896
• NM_025114.4:c.829G>A

Variant summary

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

The NM_025114.4(CEP290):​c.829G>A​(p.Glu277Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000154 in 1,297,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E277Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.02
• Publications: 18 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33849585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.829G>A	p.Glu277Lys	missense_variant	Exon 10 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.829G>A	p.Glu277Lys	missense_variant	Exon 10 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1297382 Hom.: 0 Cov.: 24 AF XY: 0.00000311 AC XY: 2 AN XY: 642670

African (AFR) AF: 0.00 AC: 0 AN: 26592

American (AMR) AF: 0.00 AC: 0 AN: 25654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23452

East Asian (EAS) AF: 0.00 AC: 0 AN: 31760

South Asian (SAS) AF: 0.00 AC: 0 AN: 70668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 0.00000198 AC: 2 AN: 1011556

Other (OTH) AF: 0.00 AC: 0 AN: 53908

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000112 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	.;M;.
PhyloP100		7.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0060	D;D;.
Sift4G	Benign	0.082	T;T;D
Polyphen		1.0	.;D;.
Vest4		0.49
MutPred		0.28		Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);
MVP		0.76
MPC		0.13
ClinPred		0.95	D
GERP RS		4.7
PromoterAI		-0.025	Neutral
Varity_R		0.40
gMVP		0.65
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45502896; hg19: chr12-88523494;