rs376016171

Variant names:

• chr12-88049016-T-C
• rs376016171
• NM_025114.4:c.*168A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_025114.4(CEP290):​c.*168A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 424,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CEP290 NM_025114.4 splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:5
• Conservation: PhyloP100: 0.00400
• 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]

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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*168A>G		splice_region	Exon 54 of 54	NP_079390.3	O15078
	CEP290	NM_025114.4	MANE Select	c.*168A>G		3_prime_UTR	Exon 54 of 54	NP_079390.3	O15078
	RLIG1	NM_001009894.3	MANE Select	c.*594T>C		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.*168A>G		splice_region	Exon 54 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.*168A>G		splice_region	Exon 28 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.*168A>G		3_prime_UTR	Exon 54 of 54	ENSP00000448012.1	O15078

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000114 AC: 31 AN: 272532 Hom.: 0 Cov.: 4 AF XY: 0.0000930 AC XY: 13 AN XY: 139860

African (AFR) AF: 0.000141 AC: 1 AN: 7100

American (AMR) AF: 0.000120 AC: 1 AN: 8364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9112

East Asian (EAS) AF: 0.00113 AC: 25 AN: 22092

South Asian (SAS) AF: 0.00 AC: 0 AN: 6370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 172250

Other (OTH) AF: 0.000232 AC: 4 AN: 17212

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67894

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000136

Asia WGS AF: 0.00349 AC: 12 AN: 3450

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome 14 (1)
-	1	-	Joubert syndrome 5 (1)
-	1	-	Leber congenital amaurosis 10 (1)
-	1	-	Meckel syndrome, type 4 (1)
-	1	-	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.55
PhyloP100		0.0040

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: rs376016171; hg19: chr12-88442793;