rs923112337

Variant names:

• chr12-88087929-T-C
• rs923112337
• NM_025114.4:c.4045A>G

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.4045A>G​(p.Met1349Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000974 in 1,027,014 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.31
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13908261).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.4045A>G	p.Met1349Val	missense	Exon 32 of 54	NP_079390.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.4045A>G	p.Met1349Val	missense	Exon 32 of 54	ENSP00000448012.1
	CEP290	ENST00000547691.8	TSL:1	c.1327A>G	p.Met443Val	missense	Exon 8 of 28	ENSP00000446905.3
	CEP290	ENST00000675476.1		c.4906A>G	p.Met1636Val	missense	Exon 34 of 56	ENSP00000502161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 37762 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.74e-7 AC: 1 AN: 1027014 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 489370

African (AFR) AF: 0.00 AC: 0 AN: 21548

American (AMR) AF: 0.00 AC: 0 AN: 8828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14148

East Asian (EAS) AF: 0.00 AC: 0 AN: 26868

South Asian (SAS) AF: 0.00 AC: 0 AN: 19824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4366

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 852190

Other (OTH) AF: 0.0000240 AC: 1 AN: 41626

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	CEP290-related disorder (1)
-	1	-	Leber congenital amaurosis (1)
-	1	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis (1)
-	1	-	Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.053
Sift	Benign	0.30	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.23		Gain of methylation at K1350 (P = 0.0325)
MVP		0.56
MPC		0.052
ClinPred		0.12	T
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.085
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs923112337; hg19: chr12-88481706;