rs184044181

Variant names:

• chr12-88054300-A-T
• rs184044181
• NM_025114.4:c.7034+40T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_025114.4(CEP290):​c.7034+40T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,277,926 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (9 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.348
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-88054300-A-T is Benign according to our data. Variant chr12-88054300-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 261854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.7034+40T>A		intron	N/A	NP_079390.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.7034+40T>A		intron	N/A	ENSP00000448012.1
	CEP290	ENST00000547691.8	TSL:1	c.4001+40T>A		intron	N/A	ENSP00000446905.3
	CEP290	ENST00000675628.1		n.8463T>A		non_coding_transcript_exon	Exon 50 of 52

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 356 AN: 151320 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000755

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.000383

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00337

GnomAD2 exomes AF: 0.00245 AC: 449 AN: 182950 AF XY: 0.00244

Gnomad AFR exome AF: 0.000407

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000415

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000107

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.00339 AC: 3823 AN: 1126496 Hom.: 9 Cov.: 16 AF XY: 0.00347 AC XY: 1984 AN XY: 571202

African (AFR) AF: 0.000795 AC: 19 AN: 23896

American (AMR) AF: 0.00181 AC: 51 AN: 28164

Ashkenazi Jewish (ASJ) AF: 0.000825 AC: 18 AN: 21806

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35888

South Asian (SAS) AF: 0.00248 AC: 169 AN: 68110

European-Finnish (FIN) AF: 0.000178 AC: 9 AN: 50434

Middle Eastern (MID) AF: 0.00263 AC: 13 AN: 4942

European-Non Finnish (NFE) AF: 0.00404 AC: 3415 AN: 844770

Other (OTH) AF: 0.00264 AC: 128 AN: 48486

GnomAD4 genome AF: 0.00235 AC: 356 AN: 151430 Hom.: 1 Cov.: 32 AF XY: 0.00218 AC XY: 161 AN XY: 73984

African (AFR) AF: 0.000753 AC: 31 AN: 41168

American (AMR) AF: 0.00191 AC: 29 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4812

European-Finnish (FIN) AF: 0.000383 AC: 4 AN: 10450

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

European-Non Finnish (NFE) AF: 0.00388 AC: 263 AN: 67858

Other (OTH) AF: 0.00334 AC: 7 AN: 2098

Alfa AF: 0.00276 Hom.: 1

Bravo AF: 0.00218

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.47
DANN	Benign	0.59
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism

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: rs184044181; hg19: chr12-88448077;