chr11-117351872-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_014956.5(CEP164):​c.277C>T​(p.Arg93Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CEP164
NM_014956.5 missense

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.84

Publications

11 publications found
Variant links:
Genes affected
CEP164 (HGNC:29182): (centrosomal protein 164) This gene encodes a centrosomal protein involved in microtubule organization, DNA damage response, and chromosome segregation. The encoded protein is required for assembly of primary cilia and localizes to mature centrioles. Defects in this gene are a cause of nephronophthisis-related ciliopathies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
CEP164 Gene-Disease associations (from GenCC):
  • ciliopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • nephronophthisis 15
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, G2P
  • Senior-Loken syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851
PP5
Variant 11-117351872-C-T is Pathogenic according to our data. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117351872-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 37296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP164NM_014956.5 linkc.277C>T p.Arg93Trp missense_variant Exon 5 of 33 ENST00000278935.8 NP_055771.4 Q9UPV0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP164ENST00000278935.8 linkc.277C>T p.Arg93Trp missense_variant Exon 5 of 33 1 NM_014956.5 ENSP00000278935.3 Q9UPV0-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151666
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000159
AC:
4
AN:
251386
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000280
AC:
41
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.0000275
AC XY:
20
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39700
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000297
AC:
33
AN:
1111986
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00000659
AC:
1
AN:
151666
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74020
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41230
American (AMR)
AF:
0.00
AC:
0
AN:
15226
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4806
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10482
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67972
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000271
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephronophthisis 15 Pathogenic:4
Jan 03, 2022
3billion
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CEP164 related disorder (ClinVar ID: VCV000037296, PMID:22863007, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22863007, PM3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.624, 3CNET: 0.904, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 03, 2012
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Mar 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 93 of the CEP164 protein (p.Arg93Trp). This variant is present in population databases (rs387907310, gnomAD 0.02%). This missense change has been observed in individuals with nephronophthisis-related ciliopathies (PMID: 22863007, 27708425). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37296). 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 disruptive. Experimental studies have shown that this missense change affects CEP164 function (PMID: 25340510). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.47
.;T;T;T;.;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;D;.;D
M_CAP
Uncertain
0.093
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Pathogenic
3.0
.;.;M;.;.;.
PhyloP100
3.8
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-8.0
D;D;D;D;D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
1.0
.;.;D;.;.;.
Vest4
0.91
MutPred
0.64
Loss of disorder (P = 0.0542);.;Loss of disorder (P = 0.0542);.;Loss of disorder (P = 0.0542);Loss of disorder (P = 0.0542);
MVP
0.96
MPC
0.53
ClinPred
0.99
D
GERP RS
6.0
PromoterAI
-0.044
Neutral
Varity_R
0.73
gMVP
0.56
Mutation Taster
=60/40
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907310; hg19: chr11-117222588; COSMIC: COSV54044695; COSMIC: COSV54044695; API