rs144206271

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000278935.8(CEP164):​c.548T>A​(p.Met183Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,569,196 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M183T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 1 hom. )

Consequence

CEP164
ENST00000278935.8 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O: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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010599554).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CEP164NM_014956.5 linkuse as main transcriptc.548T>A p.Met183Lys missense_variant 6/33 ENST00000278935.8 NP_055771.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CEP164ENST00000278935.8 linkuse as main transcriptc.548T>A p.Met183Lys missense_variant 6/331 NM_014956.5 ENSP00000278935 P1Q9UPV0-1

Frequencies

GnomAD3 genomes
AF:
0.000447
AC:
68
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000661
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000608
AC:
125
AN:
205506
Hom.:
0
AF XY:
0.000682
AC XY:
75
AN XY:
109898
show subpopulations
Gnomad AFR exome
AF:
0.000383
Gnomad AMR exome
AF:
0.0000393
Gnomad ASJ exome
AF:
0.00102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00137
Gnomad FIN exome
AF:
0.000580
Gnomad NFE exome
AF:
0.000737
Gnomad OTH exome
AF:
0.000212
GnomAD4 exome
AF:
0.000653
AC:
925
AN:
1416874
Hom.:
1
Cov.:
31
AF XY:
0.000690
AC XY:
485
AN XY:
702480
show subpopulations
Gnomad4 AFR exome
AF:
0.000191
Gnomad4 AMR exome
AF:
0.0000571
Gnomad4 ASJ exome
AF:
0.000838
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00101
Gnomad4 FIN exome
AF:
0.000387
Gnomad4 NFE exome
AF:
0.000700
Gnomad4 OTH exome
AF:
0.000514
GnomAD4 genome
AF:
0.000440
AC:
67
AN:
152322
Hom.:
0
Cov.:
32
AF XY:
0.000456
AC XY:
34
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000661
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000731
Hom.:
1
Bravo
AF:
0.000419
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000815
AC:
7
ExAC
AF:
0.000585
AC:
71
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephronophthisis 15 Uncertain:2Other:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 03, 2022- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Uncertain significance and reported on 08-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 01, 2022This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 183 of the CEP164 protein (p.Met183Lys). This variant is present in population databases (rs144206271, 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 CEP164-related conditions. ClinVar contains an entry for this variant (Variation ID: 573184). 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. -
CEP164-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 03, 2024The CEP164 c.548T>A variant is predicted to result in the amino acid substitution p.Met183Lys. To our knowledge, this variant has not been reported in individuals with CEP164-associated disorders in the literature. This variant is reported in 0.14% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 23, 2024The c.548T>A (p.M183K) alteration is located in exon 6 (coding exon 4) of the CEP164 gene. This alteration results from a T to A substitution at nucleotide position 548, causing the methionine (M) at amino acid position 183 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Retinal dystrophy Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
0.028
DANN
Benign
0.56
DEOGEN2
Benign
0.012
T;T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.051
N
LIST_S2
Benign
0.32
T;T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.55
.;N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-0.90
N;N
REVEL
Benign
0.18
Sift
Benign
0.16
T;T
Sift4G
Benign
0.077
T;T
Polyphen
0.0040
.;B
Vest4
0.16
MVP
0.067
MPC
0.16
ClinPred
0.0033
T
GERP RS
-3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.11

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; COSMIC: COSV54041419; COSMIC: COSV54041419; API