rs12144567

Variant names:

• chr1-3829950-C-A
• rs12144567
• NM_014704.4:c.1884G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-3829950-C-A
• chr1-3829950-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014704.4(CEP104):​c.1884G>T​(p.Thr628Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 1,614,140 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T628T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (44 hom.)
• Consequence: CEP104 NM_014704.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.29
• Publications: 2 publications found

Genes affected

CEP104 (HGNC:24866): (centrosomal protein 104) This gene encodes a centrosomal protein required for ciliogenesis and for ciliary tip structural integrity. The mammalian protein contains three amino-terminal hydrophobic domains, two glycosylation sites, four cysteine-rich motifs, and two regions with homology to the glutamate receptor ionotropic, NMDA 1 protein. During ciliogenesis, the encoded protein translocates from the distal tips of the centrioles to the tip of the elongating cilium. Knockdown of the protein in human retinal pigment cells results in severe defects in ciliogenesis with structural deformities at the ciliary tips. Allelic variants of this gene are associated with the autosomal-recessive disorder Joubert syndrome, which is characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. [provided by RefSeq, Feb 2016]

CEP104 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-3829950-C-A is Benign according to our data. Variant chr1-3829950-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0043 (655/152274) while in subpopulation AMR AF = 0.00745 (114/15296). AF 95% confidence interval is 0.00634. There are 3 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014704.4. 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
	CEP104	NM_014704.4	MANE Select	c.1884G>T	p.Thr628Thr	synonymous	Exon 14 of 22	NP_055519.1	O60308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP104	ENST00000378230.8	TSL:5 MANE Select	c.1884G>T	p.Thr628Thr	synonymous	Exon 14 of 22	ENSP00000367476.3	O60308-1
	CEP104	ENST00000675666.1		c.1884G>T	p.Thr628Thr	synonymous	Exon 14 of 21	ENSP00000502548.1	A0A6Q8PH69
	CEP104	ENST00000676052.1		c.1902G>T	p.Thr634Thr	synonymous	Exon 14 of 22	ENSP00000502793.1	A0A6Q8PHR0

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 655 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00644

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00440 AC: 1106 AN: 251478 AF XY: 0.00441

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00697

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00651 AC: 9520 AN: 1461866 Hom.: 44 Cov.: 33 AF XY: 0.00627 AC XY: 4559 AN XY: 727234

African (AFR) AF: 0.00125 AC: 42 AN: 33480

American (AMR) AF: 0.00660 AC: 295 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00200 AC: 107 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00780 AC: 8679 AN: 1111990

Other (OTH) AF: 0.00614 AC: 371 AN: 60396

GnomAD4 genome AF: 0.00430 AC: 655 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74442

African (AFR) AF: 0.00108 AC: 45 AN: 41566

American (AMR) AF: 0.00745 AC: 114 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00359 AC: 38 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00644 AC: 438 AN: 68028

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00374 Hom.: 1

Bravo AF: 0.00442

EpiCase AF: 0.00616

EpiControl AF: 0.00729

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	CEP104-related disorder (1)
-	-	1	Joubert syndrome 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.17
DANN	Benign	0.47
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs12144567; hg19: chr1-3746514; COSMIC: COSV100986756; COSMIC: COSV100986756;