11-117351872-C-T

Variant names:

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

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

CEP164 links:

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
CEP164	NM_014956.5 link	c.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
CEP164	ENST00000278935.8 link	c.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:

AN:

151666

Hom.:

Cov.:

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:

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:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111986

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

AN:

41230

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

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

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000271

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

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

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

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

LIST_S2

Pathogenic

0.99

D;D;D;D;.;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.0

.;.;M;.;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.59

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

GERP RS

6.0

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.73

gMVP

0.56

Mutation Taster

=60/40

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over