rs2275829

Variant names:

• chr1-3829920-T-C
• rs2275829
• NM_014704.4:c.1914A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014704.4(CEP104):​c.1914A>G​(p.Arg638Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,614,168 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (363 hom.)
• Consequence: CEP104 NM_014704.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.56
• Publications: 5 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):

• Joubert syndrome 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.82).
• BP6: Variant 1-3829920-T-C is Benign according to our data. Variant chr1-3829920-T-C is described in ClinVar as Benign. ClinVar VariationId is 475460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

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.1914A>G	p.Arg638Arg	synonymous	Exon 14 of 22	NP_055519.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP104	ENST00000378230.8	TSL:5 MANE Select	c.1914A>G	p.Arg638Arg	synonymous	Exon 14 of 22	ENSP00000367476.3
	CEP104	ENST00000675666.1		c.1914A>G	p.Arg638Arg	synonymous	Exon 14 of 21	ENSP00000502548.1
	CEP104	ENST00000676052.1		c.1932A>G	p.Arg644Arg	synonymous	Exon 14 of 22	ENSP00000502793.1

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 808 AN: 152176 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00897 AC: 2255 AN: 251494 AF XY: 0.00834

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0961

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00446 AC: 6513 AN: 1461874 Hom.: 363 Cov.: 33 AF XY: 0.00431 AC XY: 3135 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.125 AC: 4946 AN: 39696

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86256

European-Finnish (FIN) AF: 0.0152 AC: 814 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000302 AC: 336 AN: 1112000

Other (OTH) AF: 0.00384 AC: 232 AN: 60394

GnomAD4 genome AF: 0.00531 AC: 809 AN: 152294 Hom.: 38 Cov.: 33 AF XY: 0.00664 AC XY: 494 AN XY: 74452

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.108 AC: 559 AN: 5180

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4818

European-Finnish (FIN) AF: 0.0159 AC: 169 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000879 Hom.: 1

Bravo AF: 0.00464

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.58
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs2275829; hg19: chr1-3746484; COSMIC: COSV65517537; COSMIC: COSV65517537;