rs144206271

Positions:

Variant summary

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

The NM_014956.5(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 (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 1 hom. )

Consequence

CEP164
NM_014956.5 missense

Scores

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]

CEP164 links:

CEP164 (HGNC:):

CEP164 links:

Genome browser will be placed here

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
CEP164	NM_014956.5 linkuse as main transcript	c.548T>A	p.Met183Lys	missense_variant	6/33	ENST00000278935.8	NP_055771.4	Q9UPV0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP164	ENST00000278935.8 linkuse as main transcript	c.548T>A	p.Met183Lys	missense_variant	6/33	1	NM_014956.5	ENSP00000278935.3		Q9UPV0-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152204

Hom.:

Cov.:

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.:

AF XY:

0.000682

AC XY:

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.:

Cov.:

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:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

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.:

Bravo

AF:

0.000419

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 03, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - 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. -

CEP164-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The 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 submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The 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 submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

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

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

.;N

PrimateAI

Benign

0.23

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over