rs117321017

Positions:

• chr11-95813062-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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]

ACMG classification

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: 915 AN: 152172 Hom.: 5 Cov.: 32

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.: 11 AF XY: 0.00570 AC XY: 774 AN XY: 135744

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.: 46 Cov.: 32 AF XY: 0.00649 AC XY: 4721 AN XY: 726962

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.: 6 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74476

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.: 5

Bravo AF: 0.00555

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00583 AC: 708

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00919

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
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	D
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	D
MutationTaster	Benign	0.64	N;N;N;N;N
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs117321017; hg19: chr11-95546226; COSMIC: COSV100334878; COSMIC: COSV100334878;