rs200178519

Variant names:

• chr12-88049348-C-T
• rs200178519
• NM_025114.4:c.7276G>A
• CEP290 p.Asp2426Asn

Variant summary

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

The NM_025114.4(CEP290):​c.7276G>A​(p.Asp2426Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,572,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 7.13
• Publications: 2 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]

RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

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.7276G>A	p.Asp2426Asn	missense	Exon 54 of 54	NP_079390.3	O15078
	RLIG1	NM_001009894.3	MANE Select	c.*926C>T		3_prime_UTR	Exon 7 of 7	NP_001009894.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.7276G>A	p.Asp2426Asn	missense	Exon 54 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.4243G>A	p.Asp1415Asn	missense	Exon 28 of 28	ENSP00000446905.3	A0A5K1VW81
	RLIG1	ENST00000356891.4	TSL:1 MANE Select	c.*926C>T		3_prime_UTR	Exon 7 of 7	ENSP00000349358.3	Q8N999-1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000862 AC: 20 AN: 232108 AF XY: 0.0000556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000135 AC: 192 AN: 1420968 Hom.: 0 Cov.: 26 AF XY: 0.000139 AC XY: 98 AN XY: 707490

African (AFR) AF: 0.00 AC: 0 AN: 31970

American (AMR) AF: 0.000145 AC: 6 AN: 41416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4998

European-Non Finnish (NFE) AF: 0.000162 AC: 176 AN: 1085112

Other (OTH) AF: 0.000153 AC: 9 AN: 58968

GnomAD4 genome AF: 0.000197 AC: 30 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74182

African (AFR) AF: 0.0000483 AC: 2 AN: 41422

American (AMR) AF: 0.000459 AC: 7 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000295 AC: 20 AN: 67876

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.000162

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome 14 (1)
-	1	-	CEP290-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Joubert syndrome 5 (1)
-	1	-	Leber congenital amaurosis (1)
-	1	-	Leber congenital amaurosis 10 (1)
-	1	-	Meckel syndrome, type 4 (1)
-	1	-	Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)
-	1	-	not provided (1)
-	1	-	Senior-Loken syndrome 6 (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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Varity_R		0.45
gMVP		0.39
Mutation Taster		=33/67	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200178519;

hg19: chr12-88443125;