NM_025114.4:c.1991A>G

Variant names:

• chr12-88114481-T-C
• rs79705698
• NM_025114.4:c.1991A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025114.4(CEP290):​c.1991A>G​(p.Asp664Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,548,028 control chromosomes in the GnomAD database, including 1,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D664D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (161 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1363 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 5.83
• Publications: 23 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001729846).
• BP6: Variant 12-88114481-T-C is Benign according to our data. Variant chr12-88114481-T-C is described in ClinVar as Benign. ClinVar VariationId is 100592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

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.1991A>G	p.Asp664Gly	missense	Exon 20 of 54	NP_079390.3	O15078

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.1991A>G	p.Asp664Gly	missense	Exon 20 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000604024.5	TSL:1	c.1250A>G	p.Asp417Gly	missense	Exon 12 of 20	ENSP00000473863.1	S4R322
	CEP290	ENST00000547926.7	TSL:1	n.1909+617A>G		intron	N/A	ENSP00000448573.3	F8VS29

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3462 AN: 152128 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.00388

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0335 AC: 5244 AN: 156596 AF XY: 0.0294

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.0919

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0219 AC: 30498 AN: 1395780 Hom.: 1363 Cov.: 29 AF XY: 0.0211 AC XY: 14520 AN XY: 688316

African (AFR) AF: 0.00251 AC: 79 AN: 31496

American (AMR) AF: 0.0968 AC: 3396 AN: 35100

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 368 AN: 25110

East Asian (EAS) AF: 0.223 AC: 7909 AN: 35536

South Asian (SAS) AF: 0.00716 AC: 561 AN: 78352

European-Finnish (FIN) AF: 0.0255 AC: 1253 AN: 49180

Middle Eastern (MID) AF: 0.00264 AC: 15 AN: 5688

European-Non Finnish (NFE) AF: 0.0143 AC: 15390 AN: 1077386

Other (OTH) AF: 0.0264 AC: 1527 AN: 57932

GnomAD4 genome AF: 0.0228 AC: 3467 AN: 152248 Hom.: 161 Cov.: 32 AF XY: 0.0244 AC XY: 1816 AN XY: 74438

African (AFR) AF: 0.00387 AC: 161 AN: 41576

American (AMR) AF: 0.0841 AC: 1286 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.141 AC: 732 AN: 5174

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4828

European-Finnish (FIN) AF: 0.0233 AC: 247 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 873 AN: 67972

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0195 Hom.: 380

Bravo AF: 0.0266

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00316 AC: 11

ESP6500EA AF: 0.0122 AC: 94

ExAC AF: 0.0111 AC: 748

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	4	not specified (4)
-	-	2	Joubert syndrome 5 (2)
-	-	2	Retinal dystrophy (2)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Kidney disorder (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	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.011	D
Sift4G	Benign	0.085	T
Polyphen		0.20	B
Vest4		0.15
MPC		0.31
ClinPred		0.018	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.21
Mutation Taster		=79/21	polymorphism (auto)

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: rs79705698; hg19: chr12-88508258; COSMIC: COSV58351871;