rs117321017

Positions:

chr11-95813062-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 [Likely_benign]. Clinvar id is 414978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-95813062-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP57	NM_014679.5 linkuse as main transcript	c.333G>C	p.Gln111His	missense_variant	3/11	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.333G>C	p.Gln111His	missense_variant	3/11	1	NM_014679.5	ENSP00000317902		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

GnomAD3 exomes

AF:

0.00562

AC:

1411

AN:

251034

Hom.:

AF XY:

0.00570

AC XY:

774

AN XY:

135744

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 SAS exome

AF:

0.00248

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

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00371

Gnomad4 ASJ exome

AF:

0.00532

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00209

Gnomad4 FIN exome

AF:

0.00715

Gnomad4 NFE exome

AF:

0.00753

Gnomad4 OTH exome

AF:

0.00593

GnomAD4 genome

AF:

0.00601

AC:

916

AN:

152290

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00707

Gnomad4 NFE

AF:

0.00857

Gnomad4 OTH

AF:

0.00947

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CEP57: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

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

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;.

MutationTaster

Benign

0.64

N;N;N;N;N

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

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