11-117361989-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_014956.5(CEP164):ā€‹c.548T>Cā€‹(p.Met183Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,569,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M183K) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000035 ( 0 hom. )

Consequence

CEP164
NM_014956.5 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -2.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029610932).
BP6
Variant 11-117361989-T-C is Benign according to our data. Variant chr11-117361989-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1403822.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP164NM_014956.5 linkc.548T>C p.Met183Thr missense_variant Exon 6 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.548T>C p.Met183Thr missense_variant Exon 6 of 33 1 NM_014956.5 ENSP00000278935.3 Q9UPV0-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000487
AC:
1
AN:
205506
Hom.:
0
AF XY:
0.00000910
AC XY:
1
AN XY:
109898
show subpopulations
Gnomad AFR exome
AF:
0.0000639
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000353
AC:
5
AN:
1416878
Hom.:
0
Cov.:
31
AF XY:
0.00000427
AC XY:
3
AN XY:
702484
show subpopulations
Gnomad4 AFR exome
AF:
0.0000319
Gnomad4 AMR exome
AF:
0.0000286
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000129
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.13e-7
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Nephronophthisis 15 Uncertain:2
Jan 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 183 of the CEP164 protein (p.Met183Thr). This variant is present in population databases (rs144206271, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CEP164-related conditions. ClinVar contains an entry for this variant (Variation ID: 1403822). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Mar 07, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Jul 30, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
0.0030
DANN
Benign
0.19
DEOGEN2
Benign
0.0043
T;T
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0048
N
LIST_S2
Benign
0.27
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.030
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.8
.;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.45
N;N
REVEL
Benign
0.12
Sift
Benign
0.57
T;T
Sift4G
Benign
0.15
T;T
Polyphen
0.0
.;B
Vest4
0.055
MutPred
0.31
.;Loss of helix (P = 0.0123);
MVP
0.061
MPC
0.12
ClinPred
0.028
T
GERP RS
-3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.033
gMVP
0.059

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs144206271; hg19: chr11-117232705; API