chr12-94308821-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016122.3(CEP83):​c.2098G>A​(p.Gly700Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,606,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G700E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CEP83
NM_016122.3 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.42
Variant links:
Genes affected
CEP83 (HGNC:17966): (centrosomal protein 83) The protein encoded by this gene is a centriolar protein involved in primary cilium assembly. Defects in this gene have been associated with infantile nephronophthisis and intellectual disability. [provided by RefSeq, Oct 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14000192).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP83NM_016122.3 linkc.2098G>A p.Gly700Arg missense_variant Exon 17 of 17 ENST00000397809.10 NP_057206.2 Q9Y592-1Q3B787

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP83ENST00000397809.10 linkc.2098G>A p.Gly700Arg missense_variant Exon 17 of 17 1 NM_016122.3 ENSP00000380911.4 Q9Y592-1
CEP83ENST00000339839.9 linkc.2098G>A p.Gly700Arg missense_variant Exon 16 of 16 1 ENSP00000344655.5 Q9Y592-1
CEP83ENST00000552632.5 linkc.490G>A p.Gly164Arg missense_variant Exon 4 of 5 3 ENSP00000447094.1 H0YHH5
CEP83ENST00000546783.1 linkn.*6G>A downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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
GnomAD3 exomes
AF:
0.0000282
AC:
7
AN:
248600
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134876
show subpopulations
Gnomad AFR exome
AF:
0.000388
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000963
AC:
14
AN:
1454492
Hom.:
0
Cov.:
28
AF XY:
0.00000691
AC XY:
5
AN XY:
723964
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000452
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000982
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000414
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2098G>A (p.G700R) alteration is located in exon 17 (coding exon 15) of the CEP83 gene. This alteration results from a G to A substitution at nucleotide position 2098, causing the glycine (G) at amino acid position 700 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nephronophthisis 18 Uncertain:1
Aug 10, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 845600). This variant has not been reported in the literature in individuals affected with CEP83-related conditions. This variant is present in population databases (rs753799181, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 700 of the CEP83 protein (p.Gly700Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
20
DANN
Uncertain
0.98
Eigen
Benign
0.11
Eigen_PC
Benign
0.17
FATHMM_MKL
Benign
0.42
N
LIST_S2
Benign
0.58
T;.;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.8
N;N;N
REVEL
Benign
0.093
Sift
Benign
0.12
T;T;T
Sift4G
Benign
0.32
T;T;T
Vest4
0.091, 0.10
MVP
0.63
MPC
0.48
ClinPred
0.13
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.043
gMVP
0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753799181; hg19: chr12-94702597; COSMIC: COSV51570157; COSMIC: COSV51570157; API