rs143711180

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000325542.10(CEP57):c.677G>A(p.Arg226His) variant causes a missense change. The variant allele was found at a frequency of 0.000311 in 1,613,894 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts 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. R226C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 3 hom. )

Consequence

CEP57
ENST00000325542.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.05

Variant links:

Genes affected

CEP57 (HGNC:30794): (centrosomal protein 57) This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

CEP57 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009007812).

BP6

Variant 11-95818882-G-A is Benign according to our data. Variant chr11-95818882-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472259.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00155 (236/152304) while in subpopulation AFR AF= 0.00522 (217/41562). AF 95% confidence interval is 0.00465. There are 2 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP57	NM_014679.5 linkuse as main transcript	c.677G>A	p.Arg226His	missense_variant	6/11	ENST00000325542.10	NP_055494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP57	ENST00000325542.10 linkuse as main transcript	c.677G>A	p.Arg226His	missense_variant	6/11	1	NM_014679.5	ENSP00000317902		Q86XR8-1

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000438

AC:

110

AN:

250870

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.00574

Gnomad AMR exome

AF:

0.000405

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:

0.00000882

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000182

AC:

266

AN:

1461590

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00618

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.00155

AC:

236

AN:

152304

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.00189

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 2

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 23, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

CEP57-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.054

T;.;T;T;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.0090

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.69

.;N;N;.;N;.;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.014

D;D;D;D;D;D;T

Sift4G

Uncertain

0.010

D;T;D;T;T;D;T

Polyphen

1.0

.;D;D;.;D;.;.

Vest4

0.33

MVP

0.65

MPC

0.44

ClinPred

0.059

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.078

gMVP

0.23

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

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