chr11-95813062-G-C

Variant names:

• chr11-95813062-G-C
• rs117321017
• NM_014679.5:c.333G>C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 0.847
• Publications: 5 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mosaic variegated aneuploidy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 414978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	NM_014679.5	MANE Select	c.333G>C	p.Gln111His	missense	Exon 3 of 11	NP_055494.2
	CEP57	NM_001243776.2		c.306G>C	p.Gln102His	missense	Exon 4 of 12	NP_001230705.1	Q86XR8-5
	CEP57	NM_001243777.2		c.333G>C	p.Gln111His	missense	Exon 3 of 10	NP_001230706.1	Q86XR8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	ENST00000325542.10	TSL:1 MANE Select	c.333G>C	p.Gln111His	missense	Exon 3 of 11	ENSP00000317902.5	Q86XR8-1
	CEP57	ENST00000325486.9	TSL:1	c.333G>C	p.Gln111His	missense	Exon 3 of 10	ENSP00000317487.5	Q86XR8-2
	CEP57	ENST00000538658.5	TSL:1	c.333G>C	p.Gln111His	missense	Exon 3 of 7	ENSP00000445706.1	Q86XR8-3

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

GnomAD2 exomes AF: 0.00562 AC: 1411 AN: 251034 AF XY: 0.00570

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 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

African (AFR) AF: 0.00137 AC: 46 AN: 33464

American (AMR) AF: 0.00371 AC: 166 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00209 AC: 180 AN: 86212

European-Finnish (FIN) AF: 0.00715 AC: 382 AN: 53404

Middle Eastern (MID) AF: 0.00423 AC: 23 AN: 5434

European-Non Finnish (NFE) AF: 0.00753 AC: 8369 AN: 1111904

Other (OTH) AF: 0.00593 AC: 358 AN: 60346

GnomAD4 genome AF: 0.00601 AC: 916 AN: 152290 Hom.: 6 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74476

African (AFR) AF: 0.00152 AC: 63 AN: 41568

American (AMR) AF: 0.00817 AC: 125 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00707 AC: 75 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00857 AC: 583 AN: 68014

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mosaic variegated aneuploidy syndrome 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.85
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.23
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Polyphen		0.34	B
Vest4		0.36
MutPred		0.21		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
Mutation Taster		=99/1	polymorphism

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