NM_014704.4:c.2766C>T

Variant names:

• chr1-3815414-G-A
• rs750794560
• NM_014704.4:c.2766C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_014704.4(CEP104):​c.2766C>T​(p.Tyr922Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,611,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: CEP104 NM_014704.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.372
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-3815414-G-A is Benign according to our data. Variant chr1-3815414-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1584350.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.372 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000713 (104/1459306) while in subpopulation AMR AF = 0.00139 (62/44602). AF 95% confidence interval is 0.00111. There are 0 homozygotes in GnomAdExome4. There are 40 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP104	NM_014704.4	c.2766C>T	p.Tyr922Tyr	synonymous_variant	Exon 22 of 22	ENST00000378230.8	NP_055519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP104	ENST00000378230.8	c.2766C>T	p.Tyr922Tyr	synonymous_variant	Exon 22 of 22	5	NM_014704.4	ENSP00000367476.3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152264 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000274 AC: 68 AN: 247856 AF XY: 0.000209

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000482

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.0000713 AC: 104 AN: 1459306 Hom.: 0 Cov.: 31 AF XY: 0.0000551 AC XY: 40 AN XY: 725862

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00139 AC: 62 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85862

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52150

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111362

Other (OTH) AF: 0.0000663 AC: 4 AN: 60336

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152264 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74392

African (AFR) AF: 0.0000482 AC: 2 AN: 41470

American (AMR) AF: 0.000392 AC: 6 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000227 Hom.: 0

Bravo AF: 0.000166

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 25 Benign:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.30
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

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: rs750794560; hg19: chr1-3731978;