rs202159966

Variant names:

• chr12-88130414-G-T
• rs202159966
• NM_025114.4:c.523C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025114.4(CEP290):​c.523C>A​(p.Gln175Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,603,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q175Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:1
• Conservation: PhyloP100: 5.35
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17046762).

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.523C>A	p.Gln175Lys	missense	Exon 9 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.523C>A	p.Gln175Lys	missense	Exon 9 of 54	ENSP00000448012.1
	CEP290	ENST00000547926.7	TSL:1	n.523C>A		non_coding_transcript_exon	Exon 9 of 21	ENSP00000448573.3
	CEP290	ENST00000675476.1		c.523C>A	p.Gln175Lys	missense	Exon 9 of 56	ENSP00000502161.1

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

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: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000172 AC: 41 AN: 237932 AF XY: 0.000155

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000238 AC: 345 AN: 1451290 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 161 AN XY: 721502

African (AFR) AF: 0.00 AC: 0 AN: 32706

American (AMR) AF: 0.000236 AC: 10 AN: 42344

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 83384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.000295 AC: 327 AN: 1108996

Other (OTH) AF: 0.000117 AC: 7 AN: 60014

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74322

African (AFR) AF: 0.000120 AC: 5 AN: 41546

American (AMR) AF: 0.000393 AC: 6 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67922

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.000491 AC: 4

ExAC AF: 0.000149 AC: 18

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Bardet-Biedl syndrome 14 (1)
-	1	-	CEP290-related disorder (1)
-	1	-	Intellectual disability (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;C0431399:Joubert syndrome;C0687120:Nephronophthisis (1)
-	1	-	Retinal dystrophy (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	Benign	0.12
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.35
Sift	Benign	0.24	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.93
MPC		0.38
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.35
gMVP		0.21
Mutation Taster		=43/57	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: rs202159966; hg19: chr12-88524191;