rs863224794

Variant names:

• chr12-88054367-C-A
• rs863224794
• NM_025114.4:c.7007G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-88054367-C-A
• chr12-88054367-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025114.4(CEP290):​c.7007G>T​(p.Gly2336Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. G2336D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.100
• 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

LOC124902977 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.099619).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.7007G>T	p.Gly2336Val	missense	Exon 51 of 54	NP_079390.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.7007G>T	p.Gly2336Val	missense	Exon 51 of 54	ENSP00000448012.1
	CEP290	ENST00000547691.8	TSL:1	c.3974G>T	p.Gly1325Val	missense	Exon 25 of 28	ENSP00000446905.3
	CEP290	ENST00000675476.1		c.7868G>T	p.Gly2623Val	missense	Exon 53 of 56	ENSP00000502161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000810 AC: 2 AN: 246968 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458672 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725444

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.0000450 AC: 2 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110440

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.10
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.045
Sift	Benign	0.072	T
Sift4G	Benign	0.24	T
Polyphen		0.0040	B
Vest4		0.16
MutPred		0.15		Loss of ubiquitination at K2338 (P = 0.0504)
MVP		0.77
MPC		0.063
ClinPred		0.23	T
GERP RS		2.2
Varity_R		0.077
gMVP		0.14
Mutation Taster		=73/27	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: rs863224794; hg19: chr12-88448144;