11-95799275-G-C

Variant names:

• chr11-95799275-G-C
• rs577173144
• NM_014679.5:c.89G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_014679.5(CEP57):​c.89G>C​(p.Arg30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. R30W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP57 NM_014679.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.497
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-95799275-G-C is Pathogenic according to our data. Variant chr11-95799275-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191025.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14255741). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014679.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	NM_014679.5	MANE Select	c.89G>C	p.Arg30Pro	missense	Exon 2 of 11	NP_055494.2
	CEP57	NM_001243776.2		c.62G>C	p.Arg21Pro	missense	Exon 3 of 12	NP_001230705.1
	CEP57	NM_001243777.2		c.89G>C	p.Arg30Pro	missense	Exon 2 of 10	NP_001230706.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	ENST00000325542.10	TSL:1 MANE Select	c.89G>C	p.Arg30Pro	missense	Exon 2 of 11	ENSP00000317902.5
	CEP57	ENST00000325486.9	TSL:1	c.89G>C	p.Arg30Pro	missense	Exon 2 of 10	ENSP00000317487.5
	CEP57	ENST00000538658.5	TSL:1	c.89G>C	p.Arg30Pro	missense	Exon 2 of 7	ENSP00000445706.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Mosaic variegated aneuploidy syndrome 2 Uncertain:1

Feb 03, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.50
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.045	D
Polyphen		0.96	D
Vest4		0.42
MutPred		0.29		Loss of helix (P = 0.0068)
MVP		0.41
MPC		0.24
ClinPred		0.59	D
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.44
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs577173144; hg19: chr11-95532439;