1-3816298-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_014704.4(CEP104):c.2644G>T(p.Ala882Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,552,854 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 3 hom. )

Consequence

CEP104
NM_014704.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.47

Publications

2 publications found

Variant links:

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

CEP104 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006147206).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000446 (68/152310) while in subpopulation AMR AF = 0.00157 (24/15298). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP104	NM_014704.4 link	c.2644G>T	p.Ala882Ser	missense_variant	Exon 21 of 22	ENST00000378230.8	NP_055519.1	O60308-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP104	ENST00000378230.8 link	c.2644G>T	p.Ala882Ser	missense_variant	Exon 21 of 22	5	NM_014704.4	ENSP00000367476.3		O60308-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000541

AC:

AN:

160952

AF XY:

0.000401

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000594

Gnomad NFE exome

AF:

0.000671

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.000441

AC:

617

AN:

1400544

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

301

AN XY:

690952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31730

American (AMR)

AF:

0.00153

AC:

AN:

35852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25186

East Asian (EAS)

AF:

0.00

AC:

AN:

35928

South Asian (SAS)

AF:

0.00

AC:

AN:

79312

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49230

Middle Eastern (MID)

AF:

0.00212

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.000451

AC:

487

AN:

1079590

Other (OTH)

AF:

0.00107

AC:

AN:

58068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000446

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41568

American (AMR)

AF:

0.00157

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68026

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000470

Hom.:

Bravo

AF:

0.000646

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000472

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 25

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 882 of the CEP104 protein (p.Ala882Ser). This variant is present in population databases (rs185664269, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CEP104-related conditions. ClinVar contains an entry for this variant (Variation ID: 475462). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Feb 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2644G>T (p.A882S) alteration is located in exon 21 (coding exon 20) of the CEP104 gene. This alteration results from a G to T substitution at nucleotide position 2644, causing the alanine (A) at amino acid position 882 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0060

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.68

M_CAP

Benign

0.013

MetaRNN

Benign

0.0061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

2.5

PrimateAI

Benign

0.29

PROVEAN

Benign

0.28

REVEL

Benign

0.024

Sift

Benign

0.61

Sift4G

Benign

0.74

Polyphen

0.013

Vest4

0.087

MVP

0.43

MPC

0.16

ClinPred

0.032

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.12

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over