rs139110744

Positions:

chr11-95799281-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The ENST00000325542.10(CEP57):c.95C>T(p.Ser32Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,613,972 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

CEP57
ENST00000325542.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.59

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02253905).

BP6

Variant 11-95799281-C-T is Benign according to our data. Variant chr11-95799281-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539588.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000198 (290/1461810) while in subpopulation MID AF= 0.00104 (6/5764). AF 95% confidence interval is 0.000453. There are 1 homozygotes in gnomad4_exome. There are 137 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP57	NM_014679.5 linkuse as main transcript	c.95C>T	p.Ser32Phe	missense_variant	2/11	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.95C>T	p.Ser32Phe	missense_variant	2/11	1	NM_014679.5	ENSP00000317902		Q86XR8-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251190

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000198

AC:

290

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00302

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000204

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.000249

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

The c.95C>T (p.S32F) alteration is located in exon 2 (coding exon 2) of the CEP57 gene. This alteration results from a C to T substitution at nucleotide position 95, causing the serine (S) at amino acid position 32 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

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

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.047

MetaRNN

Benign

0.023

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

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.4

.;M;M;.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.17

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0090

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

Polyphen

1.0, 1.0

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

Vest4

0.56

MVP

0.48

MPC

0.25

ClinPred

0.068

GERP RS

4.0

Varity_R

0.24

gMVP

0.61

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