rs117321017
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_014679.5(CEP57):āc.333G>Cā(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 (ā ā ).
Frequency
Genomes: š 0.0060 ( 6 hom., cov: 32)
Exomes š: 0.0066 ( 46 hom. )
Consequence
CEP57
NM_014679.5 missense
NM_014679.5 missense
Scores
8
9
Clinical Significance
Conservation
PhyloP100: 0.847
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]
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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 | UniProt |
---|---|---|---|---|---|---|---|
CEP57 | NM_014679.5 | c.333G>C | p.Gln111His | missense_variant | 3/11 | ENST00000325542.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP57 | ENST00000325542.10 | c.333G>C | p.Gln111His | missense_variant | 3/11 | 1 | NM_014679.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00601 AC: 915AN: 152172Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00562 AC: 1411AN: 251034Hom.: 11 AF XY: 0.00570 AC XY: 774AN XY: 135744
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GnomAD4 exome AF: 0.00661 AC: 9663AN: 1461284Hom.: 46 Cov.: 32 AF XY: 0.00649 AC XY: 4721AN XY: 726962
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GnomAD4 genome ? AF: 0.00601 AC: 916AN: 152290Hom.: 6 Cov.: 32 AF XY: 0.00611 AC XY: 455AN XY: 74476
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ESP6500AA
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708
Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
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 | Invitae | Jan 30, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | CEP57: BS2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;D;D;D;T
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
0.34, 1.0
.;B;D;.;.;D;.
Vest4
MutPred
0.21
.;Loss of stability (P = 0.1307);Loss of stability (P = 0.1307);.;.;Loss of stability (P = 0.1307);.;
MVP
MPC
0.39
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at