NM_014679.5:c.333G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014679.5(CEP57):c.333G>C(p.Gln111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,613,574 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 46 hom. )

Consequence

CEP57
NM_014679.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.847

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

mosaic variegated aneuploidy syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
mosaic variegated aneuploidy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CEP57 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006375551).

BP6

Variant 11-95813062-G-C is Benign according to our data. Variant chr11-95813062-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00601 (916/152290) while in subpopulation NFE AF = 0.00857 (583/68014). AF 95% confidence interval is 0.008. There are 6 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP57	NM_014679.5 link	c.333G>C	p.Gln111His	missense_variant	Exon 3 of 11	ENST00000325542.10	NP_055494.2	Q86XR8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP57	ENST00000325542.10 link	c.333G>C	p.Gln111His	missense_variant	Exon 3 of 11	1	NM_014679.5	ENSP00000317902.5		Q86XR8-1

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

915

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00707

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00859

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00562

AC:

1411

AN:

251034

AF XY:

0.00570

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00670

Gnomad NFE exome

AF:

0.00849

Gnomad OTH exome

AF:

0.00638

GnomAD4 exome

AF:

0.00661

AC:

9663

AN:

1461284

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

4721

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33464

American (AMR)

AF:

0.00371

AC:

166

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00532

AC:

139

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00209

AC:

180

AN:

86212

European-Finnish (FIN)

AF:

0.00715

AC:

382

AN:

53404

Middle Eastern (MID)

AF:

0.00423

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.00753

AC:

8369

AN:

1111904

Other (OTH)

AF:

0.00593

AC:

358

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

466

932

1399

1865

2331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.00601

AC:

916

AN:

152290

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41568

American (AMR)

AF:

0.00817

AC:

125

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00373

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00707

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00857

AC:

583

AN:

68014

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00749

Hom.:

Bravo

AF:

0.00555

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00583

AC:

708

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00919

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CEP57: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CEP57 p.Gln102His variant was identified in the literature in 1 of 96 Italian patients with gastric or lobular breast cancers (Tedaldi_2019_PMID:31514334). The variant was identified in dbSNP (ID: rs117321017) and ClinVar (classified as benign by Invitae), but was not identified in LOVD 3.0 or Cosmic. The variant was identified in control databases in 1635 of 282426 chromosomes (12 homozygous) at a frequency of 0.005789 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1135 of 128908 chromosomes (freq: 0.008805), Other in 53 of 7198 chromosomes (freq: 0.007363), European (Finnish) in 167 of 25120 chromosomes (freq: 0.006648), Ashkenazi Jewish in 62 of 10366 chromosomes (freq: 0.005981), Latino in 104 of 35428 chromosomes (freq: 0.002936), South Asian in 76 of 30602 chromosomes (freq: 0.002483) and African in 38 of 24856 chromosomes (freq: 0.001529), but was not observed in the East Asian population. The p.Gln102 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Mosaic variegated aneuploidy syndrome 2

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

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

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

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

MetaRNN

Benign

0.0064

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

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.7

.;L;L;.;.;L;.

PhyloP100

0.85

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.23

Sift

Benign

0.16

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

Sift4G

Benign

0.11

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

Polyphen

0.34, 1.0

.;B;D;.;.;D;.

Vest4

0.36

MutPred

0.21

.;Loss of stability (P = 0.1307);Loss of stability (P = 0.1307);.;.;Loss of stability (P = 0.1307);.;

MVP

0.75

MPC

0.39

ClinPred

0.011

GERP RS

2.7

Varity_R

0.12

gMVP

0.42

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over